N4-phenyl-quinazoline-4 -amine derivatives and related compounds as ErbB type I receptor tyrosine kinase inhibitors for the treatment of hyperproliferative diseases

ABSTRACT

wherein B, G, A, E, R1, R3, R4, m and n are as defined herein, which are useful as type I receptor tyrosine kinase inhibitors, and methods of use thereof in the treatment of hyperproliferative disorders in mammals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No.15/599,867, filed May 19, 2017, which is a Continuation of U.S.application Ser. No. 14/034,361, filed Sep. 23, 2013, which is aDivisional of U.S. application Ser. No. 12/085,048, filed on May 15,2008, now U.S. Pat. No. 8,648,087, which is the U.S. National Phaseunder 35 U.S.C. § 371 of International Application No.PCT/US2006/044431, filed on Nov. 15, 2006, which claims priority to U.S.Provisional application No. 60/736,289, filed Nov. 15, 2005, and U.S.Provisional application No. 60/817,019, filed Jun. 28, 2006, each ofwhich is incorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION 1. Field of the Invention

This invention relates to novel inhibitors of type I receptor tyrosinekinases and related kinases, pharmaceutical compositions containing theinhibitors, and methods for preparing these inhibitors. The inhibitorsare useful for the treatment of hyperproliferative diseases, such ascancer and inflammation, in mammals and especially in humans.

2. Description of the State of the Art

The type 1 receptor tyrosine kinase family consists of four closelyrelated receptors: EGFR (ErbB1 or HER1), ErbB2 (HER2), ErbB3 (HER), andErbB4 (HER4) (Reviewed in Riese and Stem, Bioessays (1998) 20:41-48;Olayioye et al., EMBO Journal (2000) 19:3159-3167; and Schlessinger,Cell (2002) 110:669-672). These are single pass transmembraneglycoprotein receptors containing an extracellular ligand binding regionand an intracellular signaling domain. In addition, all receptorscontain an intracellular active tyrosine kinase domain with theexception of ErbB3, whose kinase domain does not exhibit enzymaticactivity. These receptors transmit extracellular signals through thecytosol to the nucleus upon activation. The activation process isinitiated by ligand binding to the extracellular domain of the receptorby one of a number of different hormones. Upon ligand binding, homo- orheterodimerization is induced, which results in the activation of thetyrosine kinase domains and phosphorylation of tyrosines on theintracellular signaling domains. Since no known ligand for ErbB2 hasbeen described and ErbB3 lacks an active kinase domain, these receptorsmust heterodimerize to elicit a response. The phosphotyrosines thenrecruit the necessary cofactors to initiate several different signalingcascades including the ras/raf/MEK/MAPK and PI3K/AKT pathways. Theprecise signal elicited will depend on what ligands are present, sincethe intracellular signaling domains differ as to what pathways areactivated. These signaling pathways lead to both cell proliferation andcell survival through inhibition of apoptosis.

Several investigators have demonstrated the role of EGFR and ErbB2 indevelopment of cancer (reviewed in Salomon, et al., Crit. Rev. Oncol.Hematol. (1995) 19:183-232: Klapper, et al., Adv. Cancer Res. (2000)77:25-79; and Hynes and Stem, Biochim. Biophys. Acta (1994)1198:165-184). Squamous carcinomas of the head, neck and lung expresshigh levels of EGFR. Also, constitutively active EGFR has been found ingliomas, breast cancer and lung cancer. ErbB2 overexpression occurs inapproximately 30% of all breast cancer. It has also been implicated inother human cancers including colon, ovary, bladder, stomach, esophagus,lung, uterus and prostate. ErbB2 overexpression has also been correlatedwith poor prognosis in human cancer, including metastasis and earlyrelapse.

The type I tyrosine kinase receptor family has been an active area ofanti-cancer research (Reviewed in Mendelsohn and Baselga, Oncogene(2000) 19:6550-6565; and Normanno et al., Endocrine-Related Cancer(2003) 10:1-21). For example, U.S. Pat. No. 6,828,320 discloses certainsubstituted quinolines and quinazolines as protein tyrosine kinaseinhibitors.

Several inhibitors of the EGFR and the ErbB2 signaling pathway havedemonstrated clinical efficacy in cancer treatment. HERCEPTIN®, ahumanized version of anti-ErbB2 monoclonal antibody, was approved foruse in breast cancer in the United States in 1998. IRESSA® and TARCEVA®are small molecule inhibitors of EGFR that are commercially available.In addition, several other antibodies and small molecules that targetthe interruption of the type I tyrosine kinase receptor signalingpathways are in clinical and preclinical development. For example,ERBITUX®, a human-murine chimeric monoclonal antibody against EGFR, isavailable for the treatment of irinotecan-refractory colorectal cancer.

SUMMARY OF THE INVENTION

This invention provides compounds that inhibit type I receptor tyrosinekinases. Such compounds have utility as therapeutic agents for diseasesthat can be treated by the inhibition of type I receptor tyrosinekinases. They may also act as inhibitors of serine, threonine, and dualspecificity kinases inhibitors. In general, the invention relates tocompounds of Formula I

and solvates, metabolites, and pharmaceutically acceptable salts andprodrugs thereof, wherein B, G, A, E, R¹, R², R³, m and n are as definedherein, wherein when said compound of Formula I is represented by theformula

and R³ is other than Q or Z wherein Q and Z are as defined herein, thenE is not a benzofuranyl, indolyl, quinazolinyl, quinolinyl, orisoquinolinyl ring.

In a further aspect, the present invention provides a method of treatingdiseases or medical conditions mediated by type I receptor tyrosinekinases which comprises administering to a warm-blooded animal aneffective amount of a compound of Formula I, or a metabolite, solvate,or pharmaceutically acceptable salt or prodrug thereof.

In a further aspect, the present invention provides a method ofinhibiting the production of type I receptor kinases which comprisesadministering to a warm-blooded animal an effective amount of a compoundof Formula I, or a metabolite, solvate, or pharmaceutically acceptablesalt or prodrug thereof.

In a further aspect, the present invention provides a method ofproviding type I receptor kinase inhibitory effect comprisingadministering to a warm-blooded animal an effective amount of a compoundof Formula I, or a metabolite, solvate, or pharmaceutically acceptablesalt or prodrug thereof.

In a further aspect, the present invention provides treating orpreventing a type I receptor kinase mediated condition, comprisingadministering an amount of a compound effective to treat or prevent saidtype I receptor kinase-mediated condition or a pharmaceuticalcomposition comprising said compound, to a human or animal in needthereof, wherein said compound is a compound of Formula I, or apharmaceutically-acceptable salt or in vivo cleavable prodrug thereof.The type I receptor kinase mediated conditions that can be treatedaccording to the methods of this invention include, but are not limitedto, hyperproliferative disorders, such as cancer of the head and neck,lung, breast, colon, ovary, bladder, stomach, kidney, skin, pancreas,leukemias, lymphomas, esophagus, uterus or prostate, among other kindsof hyperproliferative disorders.

The compounds of Formula I may be used advantageously in combinationwith other known therapeutic agents.

The invention also relates to pharmaceutical compositions comprising aneffective amount of an agent selected from compounds of Formula I or apharmaceutically acceptable prodrug, pharmaceutically active metabolite,or a pharmaceutically acceptable salt or prodrug thereof.

This invention also provides compound of Formula I for use asmedicaments in the treatment or prevention of a type I receptorkinase-mediated condition.

An additional aspect of the invention is the use of a compound ofFormula I in the preparation of a medicament for the treatment orprevention of a type I receptor kinase-mediated condition.

This invention further provides kits for the treatment or prevention ofa type I receptor kinase-mediated condition, said kit comprising acompound of Formula I, or a solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, a container, and optionally apackage insert or label indicating a treatment. The kits may furthercomprise a second compound or formulation comprising a secondpharmaceutical agent useful for treating said disease or disorder.

This invention further includes methods of preparing, methods ofseparating, and methods of purifying of the compounds of this invention.

Additional advantages and novel features of this invention shall be setforth in part in the description that follows, and in part will becomeapparent to those skilled in the art upon examination of the followingspecification, or may be learned by the practice of the invention. Theadvantages of the invention may be realized and attained by means of theinstrumentalities, combinations, compositions, and methods particularlypointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made in detail to certain embodiments of theinvention, examples of which are illustrated in the accompanyingstructures and formulas. While the invention will be described inconjunction with the enumerated embodiments, it will be understood thatthey are not intended to limit the invention to those embodiments. Onthe contrary, the invention is intended to cover all alternatives,modifications, and equivalents, which may be included within the scopeof the present invention as defined by the claims. One skilled in theart will recognize many methods and materials similar or equivalent tothose described herein, which could be used in the practice of thepresent invention. The present invention is in no way limited to themethods and materials described. In the event that one or more of theincorporated literature and similar materials differs from orcontradicts this application, including but not limited to definedterms, tem usage, described techniques, or the like, this applicationcontrols.

Definitions

The term “alkyl” as used herein refers to a saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein the alkyl radical may be optionally substitutedindependently with one or more substituents described below. Examples ofalkyl groups include, but are not limited to, methyl (Me, —CH₃), ethyl(Et, —CH₂CH₃), 1-propyl (n-Pr, n-propyl, —CH₂CH₂CH₃), 2-propyl (i-Pr,i-propyl, —CH(CH₃)₂), 1-butyl (n-Bu, n-butyl, —CH₂CH₂CH₂CH₃),2-methyl-1-propyl(i-Bu, i-butyl, —CH₂CH(CH₃)₂), 2-butyl (s-Bu, s-butyl,—CH(CH₃)CH₂CH₃), 2-methyl-2-propyl (t-Bu, t-butyl, —C(CH₃)₃), 1-pentyl(n-pentyl, —CH₂CH₂CH₂CH₂CH₃), 2-pentyl(—CH(CH₃)CH₂CH₂CH₃),3-pentyl(—CH(CH₂CH₃)₂), 2-methyl-2-butyl, (—C(CH₃)₂CH₂CH₃),3-methyl-2-butyl (—CH(CH₃)CH(CH₃)₂), 3-methyl-1-butyl (—CH₂CH₂CH(CH₃)₂),2-methyl-1-butyl(—CH₂CH(CH₃)CH₂CH₃), 1-hexyl(—CH₂CH₂CH₂CH₂CH₂CH₃),2-hexyl(—CH(CH₃)CH₂CH₂CH₂CH₃), 3-hexyl(—CH(CH₂CH₃)(CH₂CH₂CH₃)),2-methyl-2-pentyl(—CH(CH₃)₂CH₂CH₂CH₃),3-methyl-2-pentyl(—CH(CH₃)CH(CH₃)CH₂CH₃),4-methyl-2-pentyl(—CH(CH₃)CH₂CH(CH₃)₂),3-methyl-3-pentyl(—C(CH₃)(CH₂CH₃)₂),2-methyl-3-pentyl(—CH(CH₂CH₃)CH(CH₃)₂),2,3-dimethyl-2-butyl(—C(CH₃)₂CH(CH₃)₂),3,3-dimethyl-2-butyl(—CH(CH₃)C(CH₃)₃, 1-heptyl, 1-octyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

The term “alkyl” includes saturated linear or branched-chain monovalenthydrocarbon radicals of one to six carbon atoms (e.g., C₁-C₆ alkyl),wherein the alkyl radical may be optionally substituted independentlywith one or more substituents described below.

The term “alkenyl” as used herein refers to linear or branched-chainmonovalent hydrocarbon radical of two to twelve carbon atoms with atleast one site of unsaturation, i.e., a carbon-carbon, sp² double bond,wherein the alkenyl radical may be optionally substituted independentlywith one or more substituents described herein, and includes radicalshaving “cis” and “trans” orientations, or alternatively, “E” and “Z”orientations. Examples include, but are not limited to, ethylenyl orvinyl (—CH═CH₂), allyl (—CH₂CH═CH₂), 1-cyclopent-1-enyl,1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl, 1-cyclohex-1-enyl,1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.

The term “alkynyl” as used herein refers to a linear or branchedmonovalent hydrocarbon radical of two to twelve carbon atoms with atleast one site of unsaturation, i.e., a carbon-carbon, sp trible bond,wherein the alkynyl radical may be optionally substituted independentlywith one or more substituents described herein. Examples include, butare not limited to ethynyl (—C═CH) and propynyl (propargyl, —CH₂C═CH).

The terms “cycloalkyl,” “carbocyclyl,” and “carbocycle” as used hereinare interchangeable and refer to a monovalent non-aromatic, saturated orpartially unsaturated cyclic hydrocarbon radical having from three toten carbon atoms. Examples of monocyclic carbocyclic radicals include,but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl,1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl,cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,cycloundecyl and cyclododecyl. The cycloalkyl may be optionallysubstituted independently in one or more substitutable positions withvarious groups. The term “cycloalkyl” also includes polycyclic (e.g.,bicyclic and tricyclic) cycloalkyl structures, wherein the polycyclicstructures optionally include a saturated or partially unsaturatedcycloalkyl fused to a saturated or partially unsaturated cycloalkyl orheterocyclyl ring or an aryl or heteroaryl ring. Bicyclic carbocycleshaving 7 to 12 atoms can be arranged, for example, as a bicyclo[4,5],[5,5], [5,6] or [6,6] system, or as bridged systems such asbicyclo[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]nonane.

The term “heteroalkyl” as used herein refers to saturated linear orbranched-chain monovalent hydrocarbon radical of one to twelve carbonatoms, wherein at least one of the carbon atoms is replaced with aheteroatom selected from N, O, or S, and wherein the radical may be acarbon radical or heteroatom radical (i.e., the heteroatom may appear inthe middle or at the end of the radical). The heteroalkyl radical may beoptionally substituted independently with one or more substituentsdescribed herein. The term “heteroalkyl” encompasses alkoxy andheteroalkoxy radicals.

The term “heteroalkenyl” as used herein refers to linear orbranched-chain monovalent hydrocarbon radical of two to twelve carbonatoms, containing at least one double bond, e.g., ethenyl, propenyl, andthe like, wherein at least one of the carbon atoms is replaced with aheteroatom selected from N, O, or S, and wherein the radical may be acarbon radical or heteroatom radical (i.e., the heteroatom may appear inthe middle or at the end of the radical). The heteroalkenyl radical maybe optionally substituted independently with one or more substituentsdescribed herein, and includes radicals having “cis” and “trans”orientations, or alternatively, “E” and “Z” orientations.

The term “heteroalkynyl” as used herein refers to a linear or branchedmonovalent hydrocarbon radical of two to twelve carbon atoms containingat least one triple bond. Examples include, but are not limited to,ethynyl, propynyl, and the like, wherein at least one of the carbonatoms is replaced with a heteroatom selected from N, O, or S, andwherein the radical may be a carbon radical or heteroatom radical (i.e.,the heteroatom may appear in the middle or at the end of the radical).The heteroalkynyl radical may be optionally substituted independentlywith one or more substituents described herein.

The terms “heterocycle” and “heterocyclyl” as used herein are usedinterchangeably and refer to a saturated or partially unsaturatedcarbocyclic radical of 3 to 8 ring atoms in which at least one ring atomis a heteroatom independently selected from nitrogen, oxygen and sulfur,the remaining ring atoms being C, where one or more ring atoms may beoptionally substituted independently with one or more substituentsdescribed below. The radical may be a carbon radical or heteroatomradical. The term “heterocyclyl” includes heterocycloalkoxy.“Heterocyclyl” also includes radicals wherein the heterocyclyl radicalsare fused with a saturated, partially unsaturated, or fully unsaturated(i.e., aromatic) carbocyclic or heterocyclic ring. Examples ofheterocyclyl rings include, but are not limited to, pyrrolidinyl,tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl,dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino,thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl,oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl,diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl,2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl,dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl,pyrazolidinylimidazolinyl, imidazolidinyl, 3-azabicyco[3.1.0]hexanyl,3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H-indolylquinolizinyl and N-pryidyl ureas. Spiro moieties are also included withthe scope of this definition. The heterocyclyl radical may be C-attachedor N-attached where such is possible. For instance, a group derived frompyrrole may be pyrrol-1-yl (N-attached) or pyrrol-3-yl (C-attached).Further, a group derived from imidazole may be imidazol-1-yl(N-attached) or imidazol-3-yl (C-attached). Examples of heterocyclicgroups wherein 2 ring carbon atoms are substituted with oxo (═O)moieties are isoindoline-1,3-dionyl and 1,1-dioxo-thiomorpholinyl. Theheterocyclyl groups herein are unsubstituted or, as specified,substituted in one or more substitutable positions with various groups.

By way of example and not limitation, carbon bonded heterocycles arebonded at position 2, 3, 4, 5, or 6 of a pyridine, position 3, 4, 5, or6 of a pyridazine, position 2, 4, 5, or 6 of a pyrimidine, position 2,3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan,tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole,position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4,or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of anaziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6,7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of anisoquinoline. Further examples of carbon bonded heterocycles include2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-pyridazinyl,4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl,4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl 3-pyrazinyl,5-pyrazinyl, 6-pryazinyl, 2-thiazolyl, 4-thiazolyl, or 5-thiazolyl.

By way of example and not limitation, nitrogen bonded heterocycles arebonded at positon 1 of an aziridine, azetidine, pyrrole, pyrrolidine,2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline,3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline,piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of anisoindole, or isoindoline, position 4 of a morpholine, and position 9 ora carbazole, or β-carboline. Still more typically, nitrogen bondedheterocycles include 1-aziridyl, 1-azetedyl, 1-pyrrolyl, 1-imidazolyl,1-pyrazolyl, 1-piperidinyl.

The term “arylalkyl” as used herein means an alkyl moiety (as definedabove) substituted with one or more aryl moiety (also as defined above).Examples of arylalkyl radicals include aryl-C₁₋₃-alkyls such as, but notlimited to, benzyl, phenylethyl, and the like.

The term “heteroarylalkyl” as used herein means an alkyl moiety (asdefined above) substituted with a heteroaryl moiety (also as definedabove). Examples of heteroarylalkyl radicals include 5- or 6-memberedheteroaryl-C₁₋₃-alkyls such as, but not limited to, oxazolylmethyl,pyridylethyl and the like.

The term “heterocyclylalkyl” as used herein means an alkyl moiety (asdefined above) substituted with a heterocyclyl moiety (also definedabove). Examples of heterocyclylalkyl radicals include 5- or 6-memberedheterocyclyl-C₁₋₃-alkyls such as, but not limited to,tetrahydropyranylmethyl.

The term “cycloalkylalkyl” as used herein means an alkyl moiety (asdefined above) substituted with a cycloalkyl moiety (also definedabove). Examples of heterocyclyl radicals include 5- or 6-memberedcycloalkyl-C₁₋₃-alkyls such as, but not limited to, cyclopropylmethyl.

“Substituted alkyl” as used herein refers to an alkyl in which one ormore hydrogen atoms are each independently replaced with a substituent.Typical substituents include, but are not limited to F, Cl, Br, I, CN,CF₃, OR, R, ═O, ═S, ═NR, ═N⁺(O)(R), ═N(OR), ═N⁺(O)(OR), ═N—NRR′,—C(═O)R, —C(═O)OR, —C(═O)NRR′, —NRR′, —N⁺RR′R″, —N(R)C(═O)R′,—N(R)C(═O)OR′, —N(R)C(═O)NR′R″, —SR, —OC(═O)R, —OC(═O)OR, —OC(═O)NRR′,—OS(O)₂(OR), —OP(═O)(OR)₂), —OP(OR)₂, —P(═O)(OR)₂, —P(═O)(OR)NR′R″,—S(O)R, —S(O)₂R, —S(O)₂NR, —S(O)(OR), —S(O)₂(OR), —SC(═O)R, —SC(═O)OR,═O and —SC(═O)NRR′; wherein each R, R′ and R″ is independently selectedfrom H, alkyl, alkenyl, alkynyl, aryl and heterocyclyl. Alkenyl,alkynyl, allyl, saturated or partially unsaturated cycloalkyl,heteroalkyl, heterocyclyl, arylalkyl, heteroarylalkyl,heterocyclylalkyl, cycloalkylalkyl, aryl and heteroaryl groups asdescribed above may also be similarly substituted.

The term “halogen” as used herein includes fluorine (F), bromine (Br),chlorine (Cl), and iodine (I).

The term “a” as used herein means one or more.

In the compounds of the present invention, where a term such as(CR¹³R¹⁴)_(q) is used. R¹³ and R¹⁴ may vary with each iteration of qabove 1. For instance, where q is 2, the term (CR¹³R¹⁴)_(q) may —CH₂CH₂—or —CH(CH₃)C(CH₂CH₃)(CH₂CH₂CH₃)— or any number of similar moietiesfalling within the scope of the definitions of R¹³ and R¹⁴.

ErbB Inhibitors

This invention relates to compounds that are useful for inhibiting typeI receptor tyrosine kinases, such as EGFR (HER1), ErbB2 (HER2), ErbB3(HER3), ErbB4 (HER4), VEGFR2, Flt3 and FGFR. The compounds of thisinvention may also be useful as inhibitors of serine, threonine, anddual specificity kinases such as Raf, MEK, and p38. Such compounds haveutility as therapeutic agents for diseases that can be treated by theinhibition of the type I receptor tyrosine kinases signaling pathway andserine, threonine, and dual specificity kinase pathways.

In certain embodiments, this invention relates to compounds that areuseful for inhibiting type I receptor tyrosine kinases such as EGFR(HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4).

In one embodiment, this invention includes compounds of Formula I

and solvates, metabolites, and pharmaceutically acceptable saltsthereof, wherein:

A is O, C(═O), S, SO or SO₂;

G is N or C—CN;

B represents a fused 6-membered aryl ring or a fused 5-6 memberedheteroaryl ring;

E is

X is N or CH;

D¹, D² and D³ are independently N or CR¹⁹;

D⁴ and D⁵ are independently N or CR¹⁹ and D⁶ is O, S, or NR²⁰, whereinat least one of D⁴ and D⁵ is not CR¹⁹;

D⁷, D⁸, D⁹ and D¹⁰ are independently N or CR¹⁹, wherein at least one ofD⁷, D⁸, D⁹ and D¹⁰ is N;

R¹ is H or alkyl;

each R² is independently halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —SR¹⁸, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—NR¹⁴C(O)OR¹⁸, —OC(O)R¹⁵, —NR¹⁴SO₂R¹⁸, —SO₂NR¹⁵R¹⁴, —NR¹⁴C(O)R¹⁵,—C(O)NR¹⁵R¹⁴, —NR¹⁵C(O)NR¹⁵R¹⁴, —NR¹³C(NCN)NR¹⁵R¹⁴, —NR¹⁵R¹⁴, alkyl,alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl,cycloalkylalkyl, —S(O)_(p)(alkyl), —S(O)_(p)(CR¹³R¹⁴)_(q)-aryl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, saturated or partiallyunsaturated heterocyclyl, heterocyclylalkyl, —O(CR¹³R¹⁴)_(q)-aryl,—NR¹⁵(CR¹³R¹⁴)_(q)-aryl, —O(CR¹³R¹⁴)_(q)-heteroaryl,—NR¹³(CR¹³R¹⁴)_(q)-heteroaryl, —O(CR¹³R¹⁴)_(q)-heterocyclyl or—NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹³SO₂R¹⁸,—SO₂NR¹⁵R¹³, —C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹³C(O)OR¹⁸,—NR¹³C(O)R¹⁵, —C(O)NR¹⁵R¹³, —NR¹⁵R¹³, —NR¹⁴C(O)NR¹⁵R¹³,—NR¹⁴C(NCN)NR¹⁵R¹³, —OR¹⁵, aryl, heteroaryl, arylalkyl, heteroarylalkyl,saturated and partially unsaturated heterocyclyl, and heterocyclylalkyl,and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl rings may be further substituted withone or more groups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, NR¹⁵R¹³ and OR¹⁵;

each R³ is independently Q, Z, halogen, cyano, nitro, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated orpartially unsaturated cycloalkyl, saturated or partially unsaturatedheterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,trifluoromethoxy, difluoromethoxy, fluoromethoxy, trifluoromethyl,difluoromethyl, fluoromethyl, OR¹⁵, NR¹⁵R¹⁶, NR¹⁵OR¹⁶, NR¹⁵C(═O)OR¹⁸,NR¹⁵C(═O)R¹⁶, SO₂NR¹⁵R¹⁶, SR¹⁵, SOR¹⁵, SO₂R¹⁵, C(═O)R¹⁵, C(═O)OR¹⁵,OC(═O)R¹⁵), C(═O)NR¹⁵R¹⁶, NR¹⁵C(═O)NR¹⁶, R¹⁷, NR¹⁵C(═NCN)NR¹⁶R¹⁷, orNR¹⁵C(═NCN)R¹⁶,

wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl andheteroarylalkyl are optionally substituted with one or more groupsindependently selected from halogen, oxo, cyano, nitro, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated orpartially unsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,trifluoromethoxy, difluoromethoxy, fluoromethoxy, trifluoromethyl,difluoromethyl, fluoromethyl, OR¹⁵, NR¹⁵R¹⁶, NR¹⁵OR¹⁶, NR¹⁵C(═O)OR¹⁸,NR¹⁵C(═O)R¹⁶, SO₂NR¹⁵R¹⁶, SR¹⁵, SOR¹⁵, SO₂R¹⁵, C(═O)R¹⁵, C(═O)OR¹⁵,OC(═O)R¹⁵), C(═O)NR¹⁵R¹⁶, NR¹⁵C(═O)NR¹⁶R¹⁷, NR¹⁵C(═NCN)NR¹⁶R¹⁷, orNR¹⁵C(═NCN)R¹⁶, (C₁-C₄ alkyl)NR^(a)R^(b) and NR¹⁵C(O)CH₂OR^(a),

or R³ is a 5-6 membered heterocyclic ring containing from 1 to 4heteroatoms selected from N, O, S, SO and SO₂ and substituted with-M¹-M²-M³-M⁴ or -M¹-M⁵, wherein M¹ is C₁-C₄ alkyl, wherein optionally aCH₂ is replaced by a C(═O) group; M² is NR^(e) or CR^(e)R^(f); M³ isC₁-C₄ alkyl; M⁴ is CN, NR^(c)S(O)₀₋₂R^(f), S(O)₀₋₂NR^(g)R^(h),COR^(g)R^(h), S(O)₀₋₂R^(f), or CO₂R^(f), and M⁵ is NR^(g)R^(h), whereinR^(e), R^(f), R^(g) and R^(h) are independently H or C₁₋₄ alkyl, orR^(g) and R^(h) together with the nitrogen atom to which they areattached form a 5- or 6-membered ring optionally containing 1 or 2additional heteroatoms selected from N, O, S, SO and SO₂ in which anyring nitrogen atom present is optionally substituted with a C₁-C₄ alkylgroup and which ring may optionally have one or two oxo or thiooxosubstituents;

Q is

Z is selected from

and tautomers thereof;

W and V are independently O, NR⁶, S, SO, SO₂, CR⁷R⁸, CR⁸R⁹ or C═O;

W² is O or S;

Y is S, SO, SO₂, CR⁷CR⁸, or CR⁸R⁹,

provided that when W is O, NR⁶, S, SO, or SO₂, then V is CR⁸R⁹, and

when V is O, NR⁶, S, SO, or SO₂, then W and Y are each CR⁸R⁹;

R^(8b) is H or C₁-C₆ alkyl;

each R⁶, R⁸, R^(8a) and R⁹ are independently hydrogen, trifluoromethyl,alkyl, saturated or partially unsaturated cycloalkyl, saturated orpartially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, andheterocyclylalkyl are optionally substituted with one or more groupsindependently selected from oxo, halogen, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, OR¹⁵, NR¹⁵R¹⁶,SR¹⁵, S(═O)R¹⁵, SO₂R¹⁵, trifluoromethyl, difluoromethyl, fluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl,

or R⁸ and R^(8a) together with the atom to which they are attached forma 3 to 6 membered carbocyclic ring;

R⁷ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl,saturated or partially unsaturated cycloalkyl, saturated or partiallyunsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclylalkyl, —NR¹⁵SO₂R¹⁶—SO₂NR¹⁵R¹⁶, —C(O)R¹⁵,—C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶, —C(O)NR¹⁵R¹⁶,—NR¹⁵R¹⁶, —NR¹⁵C(O)NR¹⁶R¹⁷, —OR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, or SR¹⁵, whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl, areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, alkyl, alkenyl, alkynyl, saturated and partiallyunsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, cycloalkylalkyl, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —NR¹⁵SO₂R¹⁶—SO₂NR¹⁵R¹⁶, —C(O)R¹⁵, —C(O)OR¹⁵,—OC(O)R¹⁵, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶, —C(O)NR¹⁵R¹⁶, —NR¹⁵R¹⁶,—NR¹⁵C(O)NR¹⁶R¹⁷, —OR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, SR¹⁵, aryl, arylalkyl,heteroaryl, heteroarylalkyl, and heterocyclylalkyl;

R¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclylalkyl, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶, —NR¹⁵R¹⁶, or —OR¹⁵,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclylalkyl, are optionally substituted with one or more groupsindependently selected from oxo, halogen, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —NR¹⁵SO₂R¹⁶—SO₂NR¹⁵R¹⁶,—C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶,—C(O)NR¹⁵R¹⁶, —NR¹⁵R¹⁶, —NR¹⁵C(O)NR¹⁶R¹⁷, —OR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵,SR¹⁵, aryl, arylalkyl, heteroaryl, heteroarylalkyl, andheterocyclylalkyl;

or R⁶ and R⁸ together with the atoms to which they are attached form a 3to 10 membered saturated or partially unsaturated heterocyclyl ringoptionally containing one or more additional heteroatoms selected fromN, O, S, SO, SO₂ and NR⁶, wherein said carbocyclic and heterocyclicrings are optionally substituted with one or more groups independentlyselected from oxo, halogen, alkyl, alkenyl, alkynyl, saturated andpartially unsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, cycloalkylalkyl, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵, heteroaryl,arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

or R⁷ and R⁸ together with the atoms to which they are attached form a 3to 10 membered saturated or partially unsaturated cycloalkyl orheterocyclyl ring optionally containing one or more additionalheteroatoms selected from N, O, S, SO, SO₂ and NR⁶, wherein saidcarbocyclic and heterocyclic rings are optionally substituted with oneor more groups independently selected from oxo, halogen, alkyl, alkenyl,alkynyl, saturated and partially unsaturated cycloalkyl, saturated andpartially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵,heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

or R⁸ and R⁹ together with the atoms to which they are attached form a 3to 10 membered saturated or partially unsaturated cycloalkyl orheterocyclyl ring optionally containing one or more additionalheteroatoms selected from N, O, S, SO, SO₂ and NR⁶, wherein saidcarbocyclic and heterocyclic rings are optionally substituted with oneor more groups independently selected from oxo, halogen, alkyl, alkenyl,alkynyl, saturated and partially unsaturated cycloalkyl, saturated andpartially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵,heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

or R⁶ and R¹⁰ together with the atoms to which they are attached form a3 to 10 membered saturated or partially unsaturated heterocyclyl ringoptionally containing one or more additional heteroatoms selected fromN, O, S, SO, SO₂ and NR⁶, wherein said heterocyclic ring is optionallysubstituted with one or more groups independently selected from oxo,halogen, alkyl, alkenyl, alkynyl, saturated and partially unsaturatedcycloalkyl, saturated and partially unsaturated heterocyclyl,cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵, heteroaryl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl;

or R⁸ and R¹⁰ together with the atoms to which they are attached form a3 to 10 membered saturated or partially unsaturated heterocyclyl ringoptionally containing one or more additional heteroatoms selected fromN, O, S, SO, SO₂ and NR⁶ , wherein said heterocyclic ring is optionallysubstituted with one or more groups independently selected from oxo,halogen, alkyl, alkenyl, alkynyl, saturated and partially unsaturatedcycloalkyl, saturated and partially unsaturated heterocyclyl,cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵, heteroaryl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl;

each R¹² is independently halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —SR¹⁸, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—NR¹⁴C(O)OR¹⁸, —OC(O)R¹⁵—NR¹⁴SO₂R¹⁸, —SO₂NR¹⁵R¹⁴, —NR¹⁴C(O)R¹⁵,—C(O)R¹⁵R¹⁴, —NR¹³C(O)NR¹⁵R¹⁴, —NR¹³C(NCN)NR¹⁵R¹⁴, —NR¹⁵R¹⁴, alkyl,alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl,cycloalkylalkyl, —S(O)_(p)(alkyl), —S(O)_(p)(CR¹³R¹⁴)_(q)-aryl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, saturated or partiallyunsaturated heterocyclyl, heterocyclylalkyl, —O(CR¹³R¹⁴)_(q)-aryl,—NR¹⁵(CR¹³R¹⁴)_(q)-aryl, —O(CR¹³R¹⁴)_(q)-heteroaryl,—NR¹³(CR¹³R¹⁴)_(q)-heteroaryl, —O(CR¹³R¹⁴)_(q)-heterocyclyl or—NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹³SO₂R¹⁸,—SO₂NR¹⁵R¹³, —C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹³C(O)OR¹⁸,—NR¹³C(O)R¹⁵, —C(O)NR¹⁵R¹³, —NR¹⁵, R¹³, —NR¹⁴C(O)NR¹⁵R¹³,—NR¹⁴C(NCN)NR¹⁵R¹³, —OR¹⁵, aryl, heteroaryl, arylalkyl, heteroarylalkyl,saturated and partially unsaturated heterocyclyl, and heterocyclylalkyl,and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl rings may be further substituted withone or more groups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, NR¹⁵R¹³ and OR¹⁵;

R¹³ and R¹⁴ are independently hydrogen or alkyl, or

R¹³ and R¹⁴ together with the atoms to which they are attached form asaturated or partially unsaturated cycloalkyl or a saturated orpartially unsaturated heterocyclyl ring, wherein said alkyl, cycloalkyland heterocyclyl portions are optionally substituted with one or moregroups independently selected from halogen, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, oxo, OR^(a), NR^(a)R^(b),NR^(a)OR^(b), NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a),SOR^(a), SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)OR^(b), NR^(a)C(═O)NR^(b)OR^(c);

R¹⁵, R¹⁶ and R¹⁷ are independently H, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, orheterocyclylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, and heterocyclylalkyl are optionally substituted withone or more groups independently selected from alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partiallyunsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, aryl, heteroaryl, halogen, oxo, OR^(a), NR^(a)R^(b),NR^(a)OR^(b), NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a),SOR^(a), SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b), NR^(a)C(═O)NR^(b)R^(c),OC(═O)NR^(a)R^(b), and C(═O)CH₂OR^(a);

or any two of R¹⁵, R¹⁶ and R¹⁷ together with the atom to which they areattached form a heterocyclic ring optionally containing one or moreadditional heteroatoms selected from N, O, S, SO, SO₂ and NR⁶, whereinsaid heterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, aryl, OR^(a), NR^(a)R^(b),SR^(a), heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl,

or R¹³ and R¹⁵ together with the atom to which they are attached form asaturated or partially unsaturated cycloalkyl or saturated or partiallyunsaturated heterocyclyl ring, wherein said alkyl, cycloalkyl andheterocyclyl are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, oxo, OR^(a), NR^(a)R^(b), NR^(a)OR^(b),NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a), SOR^(a),SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b), and NR^(a)C(═O)NR^(b)R^(c);

R¹⁸ is CF₃, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturatedor partially unsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl,alkenyl, alkynyl, cycloalkyl, saturated or partially unsaturatedheterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl and heterocyclylalkyl are optionally substituted withone or more groups independently selected from alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partiallyunsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, aryl, heteroaryl, halogen, oxo, OR^(a), NR^(a)R^(b),NR^(a)OR^(b), NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a),SOR^(a), SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b), and NR^(a)C(═O)NR^(b)R^(c),

R¹⁵ and R¹⁸ together with the atoms to which they are attached form asaturated or partially unsaturated cycloalkyl or saturated or partiallyunsaturated heterocyclyl ring, wherein said alkyl, cycloalkyl andheterocyclyl are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, oxo, OR^(a), NR^(a)R^(b), NR^(a)OR^(b),NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a), SOR^(a),SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b), and NR^(a)C(═O)NR^(b)R^(c);

each R¹⁹ is independently H, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —SR¹⁸, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—NR¹⁴C(O)OR¹⁸, —OC(O)R¹⁵—NR¹⁴SO₂R¹⁸, —SO₂NR¹⁵R¹⁴, —NR¹⁴C(O)R¹⁵,—C(O)NR¹⁵R¹⁴, —NR¹³C(O)NR¹⁵R¹⁴, —NR¹³C(NCN)NR¹⁵R¹⁴, —NR¹⁵R¹⁴, alkyl,alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl,cycloalkylalkyl, —S(O)_(p)(alkyl), —S(O)_(p)(CR¹³R¹⁴)_(q)-aryl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, saturated or partiallyunsaturated heterocyclyl, heterocyclylalkyl, —O(CR¹³R¹⁴)_(q)-aryl,—NR¹⁵(CR¹³R¹⁴)_(q)-aryl, —O(CR¹³R¹⁴)_(q)-heteroaryl,—NR¹³(CR¹³R¹⁴)_(q)-heteroaryl, —O(CR¹³R¹⁴)_(q)-heterocyclyl or—NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹³SO₂R¹⁸,—SO₂NR¹⁵R¹³, —C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹³C(O)OR¹⁸,—NR¹³C(O)R¹⁵, —C(O)NR¹⁵R¹³, —NR¹⁵R¹³, —NR¹⁴C(O)NR¹⁵R¹³,—NR¹⁴C(NCN)NR¹⁵R¹³, —OR¹⁵, aryl, heteroaryl, arylalkyl, heteroarylalkyl,saturated or partially unsaturated heterocyclyl, and heterocyclylalkyl,and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl rings may be further substituted withone or more groups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, NR¹⁵R¹³ and OR¹⁵;

each R²⁰ is independently C₁-C₄ alkyl, saturated or partiallyunsaturated cycloalkyl, trifluoromethyl, difluoromethyl, orfluoromethyl;

R^(a), R^(b) and R^(c) are independently H, alkyl, alkenyl, alkynyl,saturated or partially unsaturated cycloalkyl, saturated or partiallyunsaturated heterocyclyl, aryl, or heteroaryl,

or NR^(a)R^(b) forms a 5-6 membered heterocyclic ring having 1-2 ringnitrogen atoms and optionally substituted with (C₁-C₃ alkyl),

or NR^(b)R^(c) forms a 5-6 membered heterocyclic ring having 1-2 ringnitrogen atoms;

j is 0, 1, 2 or 3;

m is 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, 4, or 5; and

p is 0, 1 or 2;

wherein when said compound of Formula I is represented by the formula

and R³ is other than Q or Z, then E is not a benzofuranyl, indolyl,quinazolinyl, quinolinyl, or isoquinolinyl ring.

In certain embodiments, provided are compounds of Formula I

and solvates, metabolites, and pharmaceutically acceptable saltsthereof,

wherein:

A is O, C(═O), S, SO or SO₂;

G is N or C—CN;

B represents a fused 6-membered aryl ring or a 5-6 membered heteroarylring;

E is

X is N or CH;

D¹, D² and D³ are independently N or CR¹⁹;

D⁴ and D⁵ are independently N or CR¹⁹ and D⁶ is O, S, or NR²⁰, whereinat least one of D⁴ and D⁵ is not CR¹⁹;

D⁷, D⁸, D⁹ and D¹⁰ are independently N or CR¹⁹, wherein at least one ofD⁷, D⁸, D⁹ and D¹⁰ is N;

R¹ is H or alkyl;

each R² is independently halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —SR¹⁵, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—NR¹⁴C(O)OR¹⁸, —OC(O)R¹⁵, —NR¹⁴SO₂R¹⁸, —SO₂NR¹⁵R¹⁴, —NR¹⁴C(O)R¹⁵,—C(O)NR¹⁵R¹⁴, —NR¹⁵C(O)NR¹⁵R¹⁴, —NR¹³C(NCN)NR¹⁵R¹⁴, —NR¹⁵R¹⁴, alkyl,alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl,cycloalkylalkyl, —S(O)_(p)(alkyl), —S(O)_(p)(CR¹³R¹⁴)_(q)aryl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, saturated or partiallyunsaturated heterocyclyl, heterocyclylalkyl, —O(CR¹³R¹⁴)_(q)-aryl,—NR¹⁵(CR¹³R¹⁴)_(q)-aryl, —O(CR¹³R¹⁴)_(q)-heteroaryl,—NR¹³(CR¹³R¹⁴)_(q)-heteroaryl, —O(CR¹³R¹⁴)_(q)-heterocyclyl or—NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹³SO₂R¹⁸,—SO₂NR¹⁵R¹³, —C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹³C(O)OR¹⁸,—NR¹³C(O)R¹⁵—C(O)NR¹⁵R¹³, —NR¹⁵R¹³, —NR¹⁴C(O)NR¹⁵R¹³,—NR¹⁴C(NCN)NR¹⁵R¹³, —OR¹⁵, aryl, heteroaryl, arylalkyl, heteroarylalkyl,saturated and partially unsaturated heterocyclyl, and heterocyclylalkyl,and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl rings may be further substituted withone or more groups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, NR¹⁵R¹³ and OR¹⁵;

each R³ is independently Q, Z, halogen, cyano, nitro, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated orpartially unsaturated cycloalkyl, saturated or partially unsaturatedheterocyclyl, aryl, arylalkyl. heteroaryl, heteroarylalkyl,trifluoromethoxy, difluoromethoxy, fluoromethoxy, trifluoromethyl,difluoromethyl, fluoromethyl, OR¹⁵, NR¹⁵R¹⁶, NR¹⁵OR¹⁶, NR¹⁵C(═O)OR¹⁸,NR¹⁵C(═O)R¹⁶, SO₂NR¹⁵R¹⁶, SR¹⁵, SOR¹⁵, SO₂R¹⁵, C(═O)R¹⁵, C(═O)OR¹⁵,OC(═O)R¹⁵, C(═O)NR¹⁵R¹⁶, NR¹⁵C(═O)NR¹⁶R¹⁷, NR¹⁵C(═NCN)NR¹⁶R¹⁷, orNR¹⁵C(═NCN)R¹⁶,

wherein said alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl andheteroarylalkyl are optionally substituted with one or more groupsindependently selected from halogen, oxo, cyano, nitro, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated orpartially unsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,trifluoromethoxy, difluoromethoxy, fluoromethoxy, trifluoromethyl,difluoromethyl, fluoromethyl, OR¹⁵, NR¹⁵R¹⁶, NR¹⁵OR¹⁶, NR¹⁵C(═O)OR¹⁸,NR¹⁵C(═O)R¹⁶, SO₂NR¹⁵R¹⁶, SR¹⁵, SOR¹⁵, SO₂R¹⁵, C(═O)R¹⁵, C(═O)OR¹⁵,OC(═O)R¹⁵, C(═O)NR¹⁵R¹⁶, NR¹⁵C(═O)NR¹⁶R¹⁷, NR¹⁵C(═NCN)NR¹⁶R¹⁷, andNR¹⁵C(═NCN)R¹⁶;

Q is

Z is selected from

and tautomers thereof;

W and V are independently O, NR⁶, S, SO, SO₂, CR⁷R⁸, CR⁸R⁹ or C═O;

Y is S, SO, SO₂, CR⁷CR⁸, or CR⁸R⁹,

provided that when W is O, NR⁶, S, SO, or SO₂, then V is CR⁸R⁹, and

when V is O, NR⁶, S, SO, or SO₂, then W and Y are each CR⁸R⁹;

each R⁶, R⁸, R^(8a) and R⁹ are independently hydrogen, trifluoromethyl,alkyl, saturated or partially unsaturated cycloalkyl, saturated orpartially unsaturated heterocyclyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, cycloalkyl,heterocyclyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, andheterocyclylalkyl are optionally substituted with one or more groupsindependently selected from oxo, halogen, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro, OR¹⁵, NR¹⁵R¹⁶,SR¹⁵, S(═O)R¹⁵, SO₂R¹⁵, trifluoromethyl, difluoromethyl, fluoromethyl,fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido, aryl,heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

R⁷ is hydrogen, halogen, cyano, nitro, alkyl, alkenyl, alkynyl,saturated or partially unsaturated cycloalkyl, saturated or partiallyunsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, heterocyclylalkyl, —NR¹⁵SO₂R¹⁶—SO₂NR¹⁵R¹⁶, —C(O)R¹⁵,—C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶, —C(O)NR¹⁵R¹⁶,—NR¹⁵R¹⁶, —NR¹⁵C(O)NR¹⁶R¹⁷, —OR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, or SR¹⁵, whereinsaid alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, and heterocyclylalkyl, areoptionally substituted with one or more groups independently selectedfrom oxo, halogen, alkyl, alkenyl, alkynyl, saturated and partiallyunsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, cycloalkylalkyl, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —NR¹⁵SO₂R¹⁶—SO₂NR¹⁵R¹⁶, —C(O)R¹⁵, —C(O)OR¹⁵,—OC(O)R¹⁵, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶, —C(O)NR¹⁵R¹⁶, —NR¹⁵R¹⁶,—NR¹⁵C(O)NR¹⁶R¹⁷, —OR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, or SR¹⁵, aryl, arylalkyl,heteroaryl, heteroarylalkyl, and heterocyclylalkyl;

R¹⁰ is hydrogen, alkyl, alkenyl, alkynyl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclylalkyl, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶, —NR¹⁵R¹⁶, or —OR¹⁵,wherein said alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,heterocyclylalkyl, are optionally substituted with one or more groupsindependently selected from oxo, halogen, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, —NR¹⁵SO₂R¹⁶—SO₂NR¹⁵R¹⁶,—C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹⁵C(O)OR¹⁸, —NR¹⁵C(O)R¹⁶,—C(O)NR¹⁵R¹⁶, —NR¹⁵R¹⁶, —NR¹⁵C(O)NR¹⁶R¹⁷, —OR¹⁵, —S(O)R¹⁵, —SO₂R¹⁵, orSR¹⁵, aryl, arylalkyl, heteroaryl, heteroarylalkyl, andheterocyclylalkyl;

or R⁶ and R⁸ together with the atoms to which they are attached form a 3to 10 membered saturated or partially unsaturated heterocyclyl ringoptionally containing one or more additional heteroatoms selected fromN, O, S, SO, SO₂ and NR⁶, wherein said carbocyclic and heterocyclicrings are optionally substituted with one or more groups independentlyselected from oxo, halogen, alkyl, alkenyl, alkynyl, saturated andpartially unsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, cycloalkylalkyl, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵, heteroaryl,arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

or R⁷ and R⁸ together with the atoms to which they are attached form a 3to 10 membered saturated or partially unsaturated cycloalkyl orheterocyclyl ring optionally containing one or more additionalheteroatoms selected from N, O, S, SO, SO₂ and NR⁶, wherein saidcarbocyclic and heterocyclic rings are optionally substituted with oneor more groups independently selected from oxo, halogen, alkyl, alkenyl,alkynyl, saturated and partially unsaturated cycloalkyl, saturated andpartially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵,heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

or R⁸ and R⁹ together with the atoms to which they are attached form a 3to 10 membered saturated or partially unsaturated cycloalkyl orheterocyclyl ring optionally containing one or more additionalheteroatoms selected from N, O, S, SO, SO₂ and NR⁶, wherein saidcarbocyclic and heterocyclic rings are optionally substituted with oneor more groups independently selected from oxo, halogen, alkyl, alkenyl,alkynyl, saturated and partially unsaturated cycloalkyl, saturated andpartially unsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵,heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl;

or R⁶ and R¹⁰ together with the atoms to which they are attached form a3 to 10 membered saturated or partially unsaturated heterocyclyl ringoptionally containing one or more additional heteroatoms selected fromN, O, S, SO, SO₂ and NR⁶, wherein said heterocyclic ring is optionallysubstituted with one or more groups independently selected from oxo,halogen, alkyl, alkenyl, alkynyl, saturated and partially unsaturatedcycloalkyl, saturated and partially unsaturated heterocyclyl,cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵, heteroaryl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl;

or R⁸ and R¹⁰ together with the atoms to which they are attached form a3 to 10 membered saturated or partially unsaturated heterocyclyl ringoptionally containing one or more additional heteroatoms selected fromN, O, S, SO, SO₂ and NR⁶, wherein said heterocyclic ring is optionallysubstituted with one or more groups independently selected from oxo,halogen, alkyl, alkenyl, alkynyl, saturated and partially unsaturatedcycloalkyl, saturated and partially unsaturated heterocyclyl,cycloalkylalkyl, cyano, nitro, trifluoromethyl, difluoromethyl,fluoromethyl, fluoromethoxy, difluoromethoxy, trifluoromethoxy, azido,aryl, OR¹⁵, NR¹⁵R¹⁶, SR¹⁵, heteroaryl, arylalkyl, heteroarylalkyl, andheterocyclylalkyl;

each R¹² is independently halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —SR¹⁸, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—NR¹⁴C(O)OR¹⁸, —OC(O)R¹⁵—NR¹⁴SO₂R¹⁸, —SO₂NR¹⁵R¹⁴, —NR¹⁴C(O)R¹⁵,—C(O)NR¹⁵R¹⁴, —NR¹³C(O)NR¹⁵R¹⁴, —NR¹³C(NCN)NR¹⁵R¹⁴, —R¹⁵R¹⁴, alkyl,alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl,cycloalkylalkyl, —S(O)_(p)(alkyl), —S(O)_(p)(CR¹³R¹⁴)_(q)-aryl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, saturated or partiallyunsaturated heterocyclyl, heterocyclylalkyl, —O(CR¹³R¹⁴)_(q)-aryl,—NR¹⁵(CR¹³R¹⁴)_(q)-aryl, —O(CR¹³R¹⁴)_(q)-heteroaryl,—NR¹³(CR¹³R¹⁴)_(q)-heteroaryl, —O(CR¹³R¹⁴)_(q)-heterocyclyl or—NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹³SO₂R¹⁸,—SO₂NR¹⁵R¹³, —C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹³C(O)OR¹⁸,—NR¹³C(O)R¹⁵, —C(O)NR¹⁵R¹³, —NR¹⁵R¹³, —NR¹⁴C(O)NR¹⁵R¹³,—NR¹⁴C(NCN)NR¹⁵R¹³, —OR¹⁵, aryl, heteroaryl, arylalkyl, heteroarylalkyl,saturated and partially unsaturated heterocyclyl, and heterocyclylalkyl,and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl rings may be further substituted withone or more groups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, NR¹⁵R¹³ and OR¹⁵;

R¹³ and R¹⁴ are independently hydrogen or alkyl, or

R¹³ and R¹⁴ together with the atoms to which they are attached form asaturated or partially unsaturated cycloalkyl, or saturated or partiallyunsaturated heterocyclyl ring, wherein said alkyl, cycloalkyl andheterocyclyl portions are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, oxo, OR^(a), NR^(a)R^(b), NR^(a)OR^(b),NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a), SOR^(a),SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b), and NR^(a)C(═O)NR^(b)R^(c);

R¹⁵, R¹⁶ and R¹⁷ are independently H, alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, saturated or partiallyunsaturated cycloalkyl, saturated or partially unsaturated heterocyclyl,cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, orheterocyclylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl,heterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, and heterocyclylalkyl are optionally substituted withone or more groups independently selected from alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partiallyunsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, aryl, heteroaryl, halogen, oxo, OR^(a), NR^(a)R^(b),NR^(a)OR^(b), NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a),SOR^(a), SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(a), and NR^(a)C(═O)NR^(b)R^(c),

or any two of R¹⁵, R¹⁶ and R¹⁷ together with the atom to which they areattached form a heterocyclic ring optionally containing one or moreadditional heteroatoms selected from N, O, S, SO, SO₂ and NR⁶, whereinsaid heterocyclic ring is optionally substituted with one or more groupsindependently selected from oxo, halogen, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, cycloalkylalkyl, cyano, nitro,trifluoromethyl, difluoromethyl, fluoromethyl, fluoromethoxy,difluoromethoxy, trifluoromethoxy, azido, aryl, OR^(a), NR^(a)R^(b),SR^(a), heteroaryl, arylalkyl, heteroarylalkyl, and heterocyclylalkyl,

or R¹³ and R¹⁵ together with the atom to which they are attached form asaturated or partially unsaturated cycloalkyl or saturated or partiallyunsaturated heterocyclyl ring, wherein said alkyl, cycloalkyl andheterocyclyl are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, oxo, OR^(a), NR^(a)R^(b), NR^(a)OR^(b),NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a), SOR^(a),SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b), and NR^(a)C(═O)NR^(b)R^(c);

R¹⁸ is CF₃, alkyl, alkenyl, alkynyl, heteroalkyl, heteroalkenyl,heteroalkynyl, saturated or partially unsaturated cycloalkyl, saturatedor partially unsaturated heterocyclyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl,alkenyl, alkynyl, cycloalkyl, saturated or partially unsaturatedheterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl and heterocyclylalkyl are optionally substituted withone or more groups independently selected from alkyl, alkenyl, alkynyl,heteroalkyl, heteroalkenyl, heteroalkynyl, saturated and partiallyunsaturated cycloalkyl, saturated and partially unsaturatedheterocyclyl, aryl, heteroaryl, halogen, oxo, OR^(a), NR^(a)R^(b),NR^(a)OR^(b), NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a),SOR^(a), SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b), NR^(a)C(═O)NR^(b)R^(c),

or R¹⁵ and R¹⁸ together with the atoms to which they are attached form asaturated or partially unsaturated cycloalkyl or saturated or partiallyunsaturated heterocyclyl ring, wherein said alkyl, cycloalkyl andheterocyclyl are optionally substituted with one or more groupsindependently selected from halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, oxo, OR^(a), NR^(a)R^(b), NR^(a)OR^(b),NR^(a)CO₂R^(b), NR^(a)COR^(b), SO₂NR^(a)R^(b), SR^(a), SOR^(a),SO₂R^(a), S—S—R^(a), C(═O)R^(a), C(═O)OR^(a), OC(═O)R^(a),C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(a), and NR^(a)C(═O)NR^(b)R^(c);

each R¹⁹ is independently H, halogen, cyano, nitro, trifluoromethyl,difluoromethyl, fluoromethyl, fluoromethoxy, difluoromethoxy,trifluoromethoxy, azido, —SR¹⁸, —OR¹⁵, —C(O)R¹⁵, —C(O)OR¹⁵,—NR¹⁴C(O)OR¹⁸, —OC(O)R¹⁵, —NR¹⁴SO₂R¹⁸, —SO₂NR¹⁵R¹⁴, —NR¹⁴C(O)R¹⁵,—C(O)NR¹⁵R¹⁴, —NR¹³C(O)NR¹⁵R¹⁴, —NR¹³C(NCN)NR¹⁵R¹⁴, —NR¹⁵R¹⁴, alkyl,alkenyl, alkynyl, saturated or partially unsaturated cycloalkyl,cycloalkylalkyl, —S(O)_(p)(alkyl), S(O)_(p)(CR¹³R¹⁴)_(q)-aryl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, saturated or partiallyunsaturated heterocyclyl, heterocyclylalkyl, —O(CR¹³R¹⁴)_(q)-aryl,—NR¹⁵(CR¹³ ¹⁴ )_(q)-aryl, —O(CR¹³R¹⁴)_(q)-heteroaryl,—R¹³(CR¹³R¹⁴)_(q)-heteroaryl, —O(CR¹³R¹⁴)_(q)-heterocyclyl or—NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl, wherein said alkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyland heterocyclylalkyl portions are optionally substituted with one ormore groups independently selected from oxo, halogen, cyano, nitro,trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹³SO₂R¹⁸,—SO₂NR¹⁵R¹³, —C(O)R¹⁵, —C(O)OR¹⁵, —OC(O)R¹⁵, —NR¹³C(O)OR¹⁸,—NR¹³C(O)R¹⁵, —C(O)NR¹⁵R¹³, —NR¹⁵R¹³, —NR¹⁴C(O)NR¹⁵R¹³,—NR¹⁴C(NCN)NR¹⁵R¹³, —OR¹⁵, aryl, heteroaryl, arylalkyl, heteroarylalkyl,saturated or partially unsaturated heterocyclyl, and heterocyclylalkyl,and wherein said aryl, heteroaryl, arylalkyl, heteroarylalkyl,heterocyclyl or heterocyclylalkyl rings may be further substituted withone or more groups selected from halogen, hydroxyl, cyano, nitro, azido,fluoromethyl, difluoromethyl, trifluoromethyl, alkyl, alkenyl, alkynyl,saturated and partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, NR¹⁵R¹³ and OR¹⁵;

each R²⁰ is independently C₁-C₄ alkyl, saturated or partiallyunsaturated cycloalkyl, trifluoromethyl, difluoromethyl, orfluoromethyl;

R^(a), R^(b) and R^(c) are independently H, alkyl, alkenyl, alkynyl,saturated or partially unsaturated cycloalkyl, saturated or partiallyunsaturated heterocyclyl, aryl, or heteroaryl;

j is 0, 1, 2 or 3;

m is 1, 2, 3, or 4;

n is 0, 1, 2, 3, or 4;

q is 0, 1, 2, 3, 4, or 5; and

p is 0, 1 or 2;

wherein when said compound of Formula I is represented by the formula

and R³ is other than Q or Z, then E is not a benzofuranyl, indolyl,quinazolinyl, quinolinyl, or isoquinolinyl ring.

In certain embodiments of compounds of Formula I, G is N.

In certain embodiments of compounds of Formula I, R¹ is H.

In certain embodiments of compounds of Formula I, A is O.

In certain embodiments of compounds of Formula I, A is S.

In certain embodiments of compounds of Formula I, B is a fused 6membered aryl ring.

In certain embodiments of compounds of Formula I, B is

In certain embodiments, Formula I has the structure:

wherein R¹, R², R³, G, A, E and n are as defined above.

In certain embodiments of compounds of Formula I, B is a fused 5-6membered heteroaryl ring. In particular embodiments, B is a fused thienoring.

In certain embodiment of compounds of Formula I, B is

In certain embodiments, Formula I has the structure:

wherein R¹, R², R³, G, A, E and n are as defined above.

In certain embodiments, Formula I has the structure:

wherein R¹, R², R³, G, A, E and n are as defined above.

In certain embodiments of compounds of Formula I, E is

Exemplary embodiments of E include, but are not limited to, bicyclicheteroaryl rings selected from

wherein k is 0, 1, 2, or 3. Examples of R¹² groups include, but are notlimited to, amino, C₁-C₄ alkoxy, saturated or partially unsaturatedcycloalkyl, CN, trifluoromethyl, difluoromethyl, and fluoromethyl.Example of R¹⁹ groups include, but are not limited to, H, amino, C₁-C₄alkoxy, saturated or partially unsaturated cycloalkyl, CN,trifluoromethyl, difluoromethyl, and fluoromethyl. Examples of R²⁰include, but are not limited to, C₁-C₄ alkyl, saturated or partiallyunsaturated cycloalkyl, trifluoromethyl, difluoromethyl, andfluoromethyl.

In other embodiments, R¹² is halogen.

In other embodiments, R²⁰ is H.

In particular embodiments, R¹² is H.

In certain embodiments, R¹⁹ is H or C₁-C₆ alkyl. In particularembodiments, R¹⁹ is H or methyl.

In certain embodiments, R²⁰ is H or C₁-C₆ alkyl. In particularembodiments, R²⁰ is H, methyl or ethyl.

In particular embodiments, E is selected from the structures:

In certain embodiments of compounds of Formula I, E is

In one embodiment, at least one of D¹, D² and D³ is N.

Exemplary embodiments of E further include heteroaryl rings selectedfrom, but not limited to.

wherein each R¹⁹ group is independent of the other. Examples of R¹²groups include, but are not limited to, amino, C₁-C₄ alkoxy, saturatedor partially unsaturated cycloalkyl, CN, trifluoromethyl,difluoromethyl, and fluoromethyl. Example of R¹⁹ groups include, but arenot limited to, H, amino, C₁-C₄ alkoxy, saturated or partiallyunsaturated cycloalkyl, CN, trifluoromethyl, difluoromethyl, andfluoromethyl.

In certain embodiments, R¹² is halogen. In certain embodiments, j is 0or 1. A particular example for R¹² is F.

In certain embodiments, R¹⁹ is H, C₁-C₆ alkyl, or halogen. Particularexamples for R¹⁹ include H, methyl, Cl, and Br.

Particular examples of E include:

In one embodiment the compounds of Formula I are selected from compoundswherein E is selected from the groups E1, E2, E3, E4, E5, E6, E7 and E8:

In certain embodiments, E is selected from the groups E1, E2 and E3, andj is 0 or 1. In certain embodiments of the groups E1, E2 and E3, R¹² ishalogen. In certain embodiments of the groups E1, E2 and E3, R¹⁹ isselected from H, halogen or C₁-C₆ alkyl. In certain embodiments of thegroups E1, E2 and E3, R²⁰ is H. Particular examples of ErbB2 selectivecompounds include compounds of Formula I wherein E is selected from thegroups

In another embodiment, provided are compounds of Formula I wherein E isselected from E1, E2 and E3, provided that R³ of formula I is other than—NR¹⁵C(═O)(CH═CH)R^(16a) when R^(16a) represents H, alkyl, alkenyl,alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturated orpartially unsaturated cycloalkyl, saturated or partially unsaturatedheterocyclyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, or heterocyclylalkyl, wherein said alkyl, alkenyl,alkynyl, cycloalkyl, heterocyclyl, cycloalkylalkyl, aryl, arylalkyl,heteroaryl, heteroarylalkyl, and heterocyclylalkyl are optionallysubstituted with one or more groups independently selected from alkyl,alkenyl, alkynyl, heteroalkyl, heteroalkenyl, heteroalkynyl, saturatedand partially unsaturated cycloalkyl, saturated and partiallyunsaturated heterocyclyl, aryl, heteroaryl, halogen, oxo, OR^(a),NR^(a)R^(b), NR^(a)OR^(b), NR^(a)CO₂R^(b), NR^(a)COR^(b),SO₂NR^(a)R^(b), SR^(a), SOR^(a), SO₂R^(a), S—S—R^(a), C(═O)R^(a),C(═O)OR^(a), OC(═O)R^(a), C(═O)NR^(a)R^(b), NR^(a)C(═O)R^(b),NR^(a)C(═O)NR^(b)R^(c), OC(═O)NR^(a)R^(b), and C(═O)CH₂OR^(a). Certaincompounds belonging to this subgroup have been found to be highly potentinhibitors of ErbB2 and are highly selective for ErbB2 over EGFR. Asused herein, the term “highly selective” refers to a compound whereinthe IC₅₀ for EGFR is at least 20 fold higher than the IC₅₀ for ErbB2 asdetermined by the cellular ErbB2 and EGFR phosphorylation assaysdescribed in Examples B and C Particular compounds of this inventionwere found to have an IC₅₀ for EGFR that is at least 50 fold higher thanthe IC₅₀ for ErbB2. As a further example, particular compounds of thisinvention were found to have an IC₅₀ for EGFR that is at least 100 foldhigher than the IC₅₀ for ErbB2.

Accordingly, this invention provides compounds of Formula I which arehighly potent ErbB2 inhibitors and are highly selective for ErbB2relative to EGFR. Such compounds would allow treatment of cancers whichcan be treated by inhibiting ErbB2, for example cancers which express oroverexpress ErbB2, in a relatively selective manner, thereby minimizingpotential side effects associated with the inhibition of other kinasessuch as EGFR.

However, compounds of Formula I where R³ is —NR¹⁵C(═O)(CH═CH)R^(16a) andR^(16a) represents H or a substituted or unsubstituted C₂-C₆ alkyl werefound to be inhibitors of both ErbB2 and EGFR. In addition, suchcompounds are believed to bind irreversibly to ErbB2 and EGFR.

In certain embodiments of compounds of Formula I, m is 1.

In certain embodiments of compounds of Formula I, R³ is OR¹⁵. In certainembodiments, R¹⁵ is alkyl, alkenyl or alkynyl, wherein said alkyl,alkenyl and alkynyl are optionally substituted with one or more groupsindependently selected from saturated and partially unsaturatedcycloalkyl, heteroaryl, saturated and partially unsaturatedheterocyclyl, OR^(a), SO₂R^(a), and NR^(a)R^(b).

In certain embodiments of compounds of Formula I, R³ is OR¹⁵ and RR¹⁵ is

(i) H;

(ii) C₃-C₆ cycloalkyl optionally substituted with OR^(a);

(iii) cycloalkylalkyl;

(iv) C₁-C₆ alkyl optionally substituted with one or two groupsindependently selected from —OR^(a), —OC(O)R^(a), —CO₂R^(a), —SO₂R^(a),—SR^(a), —C(O)NR^(a)R^(b), —NR^(a)R^(b), —NR^(a)C(O)R^(b),—OC(O)NR^(a)R^(b), and NR^(a)C(O)NR^(b)R^(c);

(v) a 5-6 membered heterocyclic ring having a ring heteroatom selectedfrom N and O and optionally substituted with —C(O)R^(a), C₁-C₆ alkyl,—C(O)NR^(a)R^(b), —SO₂R^(a), or C(O)CH₂OR^(a);

(vi) heterocyclylalkyl, wherein said heterocyclic portion is a 5-6membered ring having 1 or 2 ring heteroatoms independently selected fromN and O and is optionally substituted with C₁-C₆ alkyl, halogen, OR^(a)or oxo;

(vii) a 5-6 membered heteroaryl ring having from 1 to three ringnitrogen atoms and optionally substituted with C₁-C₆ alkyl or halogen;or

(viii) heteroarylalkyl, wherein said heteroaryl portion is a 5-6membered ring having 1-2 ring nitrogen atoms and is optionallysubstituted with C₁-C₆ alkyl.

In certain embodiments, R³ is OH.

Examples of OR¹⁵ when R¹⁵ represents a C₃-C₆ cycloalkyl group optionallysubstituted by OR^(a) wherein R^(a) represents H or C₁-C₆ alkyl includecyclohexanoxy and cyclopentanoxy groups optionally substituted with OH,for example, 2-hydroxycyclopentoxy.

Examples of OR¹⁵ when R¹⁵ represents a cycloalkylalkyl group include—O—(C₃-C₆ cycloalkyl)(CH₂)_(p) wherein p is 1, 2, or 3. A particularexample is 1-cyclopropylmethoxy.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group include CH₃O—and CH₃CH₂O—.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith one or two OR^(a) groups and R^(a) represents H, C₁-C₆ alkyl orbenzyl include CH₃O(CH₂)₂O—, CH₃CH₂O(CH₂)₂O—, HO(CH₂)₂O—,HOCH₂CH(OH)CH₂O—, CH₃CH(OH)CH₂O—, HOC(CH₃)₂CH₂O—, (PhCH₂O)CH₂CH₂O—, and(PhCH₂)OCH₂CH(OH)CH₂O—.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —OC(O)R^(a) include —O—(CH₂)_(p)OC(O)R^(a) wherein p is 1-6 andR^(a) is H or C₁-C₆ alkyl. A particular example is —O—(CH₂)₂OC(O)CH₃.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —CO₂R^(a) include —O—(CH₂)_(p)OC(O)R^(a) wherein p is 1-6 and R^(a)is H or C₁-C₆ alkyl. A particular example is —O—(CH₂)CO₂CH₃.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —SO₂R^(a) include —O—(CH₂)_(p)SO₂R^(a) wherein p is 1-6 and R^(a)is C₁-C₆ alkyl. A particular example is —O(CH₂)₃SO₂CH₃.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —SR^(a) include O—(CH₂)_(p)SR^(a) wherein p is 1-6 and R^(a) isC₁-C₆ alkyl. A particular example is —O(CH₂)₃SCH₃.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —OC(O)R^(a)R^(b) include —O—(CH₂)_(p)C(O)NR^(a)R^(b) wherein p is1-6 and R^(a) and R^(b) are independently H C₁-C₆ alkyl or NR^(a)R^(b)represents a 5-6 membered heterocycle having 1-2 ring nitrogen atoms andoptionally substituted with C₁-C₆ alkyl. Particular examples of OR¹⁵include (CH₃)₂NC(O)CH₂O—, CH₃NHC(O)CH₂O—, NH₂C(O)CH₂O—, and

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —NR^(a)C(O)R^(b) include —O(CH₂)_(p)NR^(a)C(O)R^(b) wherein p is1-6 and R^(a) and R^(b) are independently H or C₁-C₆ alkyl. Particularexamples or OR¹⁵ include —O(CH₂)₂NHC(O)CH₃ and —O(CH₂)₂NHC(O)CH₂CH₃.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —NR^(a)R^(b) include —O—(CH₂)_(p)NR^(a)R^(b) wherein p is 1-6 andR^(a) and R^(b) are independently H or C₁-C₆ alkyl (for example methylor ethyl). Particular examples of OR¹⁵ include —O(CH₂)₃N(CH₃)₂ and—O(CH₂)₂N(CH₃)₂.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —OC(O)N^(a)R^(b) include —O—(CH₂)_(p)—OC(O)NR^(a)R^(b) wherein p is1-6 and R^(a) and R^(b) are independently H or C₁-C₆ alkyl. A particularexample is —O(CH₂)₂OC(O)N(CH₃)₂.

Examples of OR¹⁵ when R¹⁵ represents a C₁-C₆ alkyl group substitutedwith —NR^(a)C(O)NR^(b)R^(c) include —O—(CH₂)_(p)NR^(a)C(O)NR^(b)R^(c)wherein p is 1-6, and R^(a) and R^(b) are independently H or C₁-C₆alkyl, and R^(c) is H, C₁-C₆ alkyl or —O(C₁-C₆ alkyl), or NR^(b)R^(c)represents a 5-6 membered heterocycle having 1-2 ring nitrogen atoms(for example pyrrolidinyl). Particular examples of OR¹⁵ include

Examples of OR¹⁵ when R¹⁵ represents a 5-6 membered heterocyclic ringhaving a ring heteroatom selected from N and O and optionallysubstituted with —C(O)R^(a), C₁-C₆ alkyl, oxo, —C(O)NR^(a)R^(b),—SO₂R^(a), or —C(O)CH₂OR^(a) include pyrrolidinyl, piperidinyl, andtetrahydro-2H-pyranyl ring optionally substituted with —C(O)(C₁-C₆alkyl), oxo, C₁-C₆ alkyl, —C(O)N(C₁-C₆)alkyl)₂,—SO₂(C₁-C₆ alkyl), and—C(O)CH₂O(C₁-C₆ alkyl). Particular examples include

Examples of OR¹⁵ when R¹⁵ represents a heterocyclylalkyl group includeO-Hetcyc)(CH₂)_(p) wherein p is 1-6 and Hetcyc represents a 5-6 memberedheterocyclic ring having 1-2 ring nitrogen atoms and optionallysubstituted with one or two groups selected from C₁-C₆ alkyl, halogen,OH, O—(C₁-C₆ alkyl) and oxo. Examples of the heterocyclic ring includepyrrolidinyl, piperidinyl, morpholinyl, tetrahydrofuranyl, pyrazinyl,and imidazolidinyl rings optionally substituted with one or two groupsindependently selected from methyl, F, OH and oxo. Particular examplesof OR¹⁵ include

An example of OR¹⁵ when R¹⁵ represents a heteroaryl group includesgroups wherein the heteroaryl is a pyridinyl group optionallysubstituted with C₁-C₆ alkyl or halogen. Particular examples include2-methylpyridin-4-yloxy, 2-chloropyridin-4-yloxy, and2-methylpyridin-4-yloxy.

An example of OR¹⁵ when R¹⁵ represents a heteroarylalkyl group includes—O—(CH₂)_(p)(heteroaryl) wherein p is 1-6 and the heteroaryl group isoptionally substituted with C₁-C₆ alkyl. Examples of the heteroarylgroup include 5-6 membered rings having 1 to 3 nitrogen atoms, forexample imidazolyl and 1,2,4-triazolyl. Particular examples of OR¹⁵include

In certain embodiments, R³ is a 5 membered heterocyclic ring bonded tothe B ring through a nitrogen atom and optionally having a second ringheteroatom selected from N and O. In certain embodiments, theheterocyclic ring is substituted with one or two groups independentlyselected from C₁-C₆ alkyl, oxo and (CH₂)₁₋₂NR^(a)R^(b), wherein R^(a)and R^(b) are independently H or C₁-C alkyl. Particular examples of OR¹⁵include

In certain embodiments, R³ is a 5-6 membered heteroaryl ring having 1-3nitrogen atoms, wherein said heteroaryl is linked to the B ring by aring nitrogen atom. An example includes 1H-pyrazolyl, for example1H-pyrazol-1-yl.

In certain embodiment of compounds of Formula I, R³ is Z. In certainembodiments, Z is selected from

and tautomers thereof. Examples of tautomers of the above Z groupsinclude those wherein R⁶ is hydrogen, and can be represented by thefollowing structures:

In certain embodiments, Z is selected from:

In certain embodiments, W is O or S.

In certain embodiments, W² is O or S.

In certain embodiments, V is CR⁸R⁹.

In certain embodiments, Z is selected from:

In certain embodiments, R⁶ is H or C₁-C₆ alkyl.

In certain embodiments, R⁸ and R^(8a) are independently H or C₁-C₆ alkyloptionally substituted with OR^(a) wherein R^(a) is H or C₁-C₆ alkyl. Inother embodiments, R⁸ and R^(8a) together with the atom to which theyare attached form a C₃-C₆ cycloalkyl ring.

In certain embodiments, Z is selected from

In certain embodiments, R³ is NR¹⁵C(═O)R¹⁶. Examples of R¹⁶ include, butare not limited to, alkyl, alkenyl or alkynyl, wherein said alkyl,alkenyl and alkynyl are optionally substituted with NR^(a)R^(b).

In other embodiments, R³is —NR¹⁵C(═O)R¹⁶ wherein R¹⁵ is H or methyl andR¹⁶ represents C₂-C₆ alkenyl optionally substituted with NR^(a)R^(b).Examples include —NR¹⁵C(═O)—CH═CH₂R^(16a) wherein R^(16a) represents Hor a substituted or unsubstituted C₁-C₆ alkyl. Particular examples of R³include —NHC(═O)—CH═CH₂ and —NHC(═O)—CH═CHCH₂N(CH₃)₂.

In other embodiments, R³ is —NR¹⁵C(═O)R¹⁶ wherein R¹⁵wherein R¹⁵is H ormethyl and R¹⁶ represents a 5-6 membered heterocyclic ring having one ortwo ring heteroatoms and optionally substituted with C₁-C₆ alkyl.Examples of heterocyclic rings include piperidinyl, tetrahydrofuranyl,and tetrahydropyranyl rings optionally substituted with C₁-C₆ alkyl.Particular examples of R³ include

In other embodiments, R³ is —NR¹⁵C(═O)R¹⁶ wherein R¹⁵ represents H ormethyl and R¹⁶ represents C₁-C₆ alkyl optionally substituted with one ormore groups independently selected from C₁-C₆ alkyl and OR^(a). Incertain embodiments, R^(a) is H or C₁-C₆ alkyl. Particular examples ofR³ include CH₃C(O)NH—, (CH₃)₂C(O)NH—, CH₃CH₂C(O)N(CH₃)—, CH₃OCH₂C(O)NH—,CH₃OCH₂C(O)N(CH₃)—, CH₃CH(OCH₃)C(O)NH—, CH₃OCH₂CH₂C(O)NH—,CH₃OCH(CH₃)C(O)NH—, and CH₃OCH₂CH(CH₃)C(O)NH—.

In certain embodiments, R³ is —C(═O)NR¹⁵R¹⁶. In certain embodiments, R¹⁵and R¹⁶ independently are H or C₁-C₆ alkyl. A particular example of R³is —C(═O)N(CH₃)₂. In other embodiments, R¹⁵ and R¹⁶ together with theatom to which they are attached form a 6 membered heterocyclic ringoptionally having a second heteroatom selected from N and O andoptionally substituted with C₁-C₆ alkyl. Examples of the heterocyclicring include piperazinyl or morpholinyl optionally substituted withmethyl. Particular embodiments of R³ include —C(═O)(4-morpholinyl) and—C(═O)(1-methylpiperazin-4-yl).

In certain embodiments, R³ is SO₂R¹⁵. In certain embodiments, R¹⁵ isC₁-C₆ alkyl or a phenyl group optionally substituted with C₁-C₆ alkyl.Particular examples of R³ include 4-methylbenzenesulfonate orethanesulfonate.

In certain embodiments, R³ is SOR¹⁵. In certain embodiments, R¹⁵ isC₁-C₆ alkyl. A particular example of R³ is ethysulfinyl.

In certain embodiments, R³ is SR¹⁵. In certain embodiments, R¹⁵ is C₁-C₆alkyl. A particular example of R³ is EtS—.

In certain embodiments, R³ is halogen. A particular example of R³ isbromide.

In certain embodiments, R³ is —CO₂R¹⁵. In certain embodiments, R¹⁵ is a6 membered heterocyclic ring having one or two ring nitrogen atoms (forexample piperidinyl or piperazinyl). In certain embodiments, theheterocyclic ring is substituted with C₁-C₆ alkyl (for example methyl).A particular example of R³ is —CO₂(1-methylpiperazinyl).

In certain embodiments, R³ is a substituted or unsubstituted C₁-C₆ alkylgroup. In certain embodiments, the alkyl group is substituted with OR¹⁵,wherein R¹⁵ is H or (C₁-C₆ alkyl), such as —(C₁-C₆ alkyl)OH and —(C₁-C₆alkyl)O(C₁-C₆ alkyl). Particular examples of R³ include —(CH₂)₃OH and—(CH₂)₃OCH₃.

In certain embodiments, R³ is a C₃-C₆ alkynyl group. In certainembodiments, the alkynyl group is substituted with OR¹⁵. In certainembodiments, R¹⁵ is H or (C₁-C₆ alkyl). Particular examples of R³include

In certain embodiments, R³ is a C₃-C₆ alkynyl group substituted with—NR¹⁵C(O)CH₂OR^(a). In certain embodiments, R¹⁵ is H or C₁-C₆ alkyl. Incertain embodiments, R^(a) is H or C₁-C₆ alkyl. A particular example ofR³ is

In certain embodiments, R³ is a C₃-C₆ alkynyl group substituted with a 6membered heterocyclic ring having one or two ring heteroatomsindependently selected from N, O, and SO₂. In certain embodiments, theheterocyclic ring has at least one ring nitrogen atom and is attached tothe alkynyl group through the nitrogen atom. Particular examples of R³include

In certain embodiments, R³ is a —NR¹⁵C(O)NR¹⁶R¹⁷ group. In certainembodiments, R¹⁵, R¹⁶ and R¹⁷ are independently H or C₁-C₆ alkyl.Particular examples of R³ include

In certain embodiments, R³ is a —NR¹⁵C(O)NR¹⁶R¹⁷ group wherein R¹⁵ is Hor C₁-C₆ alkyl and R¹⁶ and R¹⁷ together with the nitrogen atom to whichthey are attached form a 5-6 membered heterocyclic ring optionallyhaving a second heteroatom selected from N and O. Examples includepyrrolidinyl, morpholinyl and piperazinyl rings. In certain embodiments,the heterocyclic ring is substituted with C₁-C₆ alkyl. Particularexamples of R³ include

In certain embodiments, R³ is a heterocyclylalkyl group. Examplesinclude (CH₂)_(p)-(hetCyc) wherein p is 1-6 and hetCyc is a 6 memberedheterocyclic ring having a ring nitrogen atom and optionally having asecond ring atom selected from N and SO₂. A particular example of R³ is

In certain embodiments, R³ is a 5-6 membered heterocyclic ringcontaining from 1 to 4 heteroatoms selected from N, O, S, SO and SO₂ andsubstituted with the group M¹-M²-M³-M⁴, wherein M¹, M², M³ and M⁴ are asdefined herein.

In certain embodiments, the 5-6 membered heterocyclic ring is furanyl,dihydrofuranyl, thienyl, imidazolyl, tetrazolyl, triazolyl, pyridinyl,pyrrolyl, pyrimidinyl, isoaxazoleyl or oxadiazolyl. In a particularembodiment, the heterocyclic ring is furanyl.

In certain embodiments, M¹ is CH₂, CH₂CH₂, C(O), or CH₂C(O). Inparticular embodiments. M¹ is CH₂.

In certain embodiments, M² is NH or N(C₁-C₆ alkyl). In particularembodiments, M¹² is NH or NMe.

In certain embodiments, M³ is methylene, ethylene or propylene.

In certain embodiments, M⁴ is SOR^(f), SO₂R_(f), NR^(e)SO₂R^(f),SO₂NR^(g)R^(h), CO₂R_(f), or CONR^(g)R^(h). wherein R^(f), R^(g) andR^(h) are independently H or C₁-C₄ alkyl.

Particular examples of R³ when it is represented by a 5-6 memberedheterocyclic ring substituted with the group M¹-M²-M³-M⁴ include:

In a particular embodiment, R³ is

In certain embodiments, n is 1 and R² is halogen, CN, trifluoromethyl,difluoromethyl, fluoromethyl, C₁-C₄-alkyl, C₁-C₄-alkoxy, or cycloalkyl.

In certain embodiments, the phrase “R⁶ and R⁸ together with the atoms towhich they are attached form a 3 to 10 membered saturated or partiallyunsaturated heterocyclic ring” refers to a ring formed from an R⁶ and R⁸radical attached to different atoms on the same functional group, suchas in a Q or Z group as defined above. The heterocyclic ring formed canbe a fused ring or a spirocyclic ring.

In certain embodiments, the phrase “R⁷ and R⁸ together with the atoms towhich they are attached form a 3 to 10 membered saturated or partiallyunsaturated cycloalkyl or heterocyclic ring” refers to a spirocyclicring formed from an R⁷ and R⁸ radical attached to the same carbon atom,for example such as in a Z group as defined above wherein W is CR⁷R⁸. Inother embodiments, the ring can be a fused ring formed by the R⁷ atomthat is part of the CR⁷R⁸ group and an R⁸ atom attached to an adjacentcarbon on the Z group.

In certain embodiments, the phrase “R⁸ and R⁹ together with the atoms towhich they are attached form a 3 to 10 membered saturated or partiallyunsaturated cycloalkyl or heterocyclyl ring” refers to a spirocyclicring formed from an R⁸ and R⁹ radical attached to the same carbon atom,for example such as in a Z group as defined above wherein V is CR⁸R⁹. Inother embodiments, the ring can be a fused ring formed by the R⁹ atom ofthe CR⁸R⁹ group and an R⁸ atom attached to an adjacent carbon on the Zgroup.

In certain embodiments, the phrase “R⁶ and R¹⁰ together with the atomsto which they are attached form a 3 to 10 membered saturated orpartially unsaturated heterocyclyl ring” refers to a ring formed by theNR⁶ and the R¹⁰ groups on the group Q as defined above.

In certain embodiments, the phrase “R⁸ and R¹⁰ together with the atomsto which they are attached form a 3 to 10 membered saturated orpartially unsaturated heterocyclyl ring” refers to a ring formed by theN—R⁸ and the R¹⁰ atoms on the group Q as defined above.

In certain embodiments, the phrase “R¹³ and R¹⁴ together with the atomsto which they are attached form a saturated or partially unsaturatedcycloalkyl or a saturated or partially unsaturated heterocyclyl ring”refers to a carbocyclic ring formed from an R¹³ and R¹⁴ radical attachedto the same carbon atom, such as in a group having the formula—S(O)_(p)(CR¹³R¹⁴)_(q)—, —O(CR¹³R¹⁴)_(q)-aryl, —NR¹⁵(CR¹³R¹⁴)_(q)-aryl,—O(CR¹³R¹⁴)_(q)-heteroaryl, —NR¹³(CR¹³R¹⁴)_(q)-heteroaryl,—O(CR¹³R¹⁴)_(q)-heterocyclyl or —NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl, or to aheterocyclic ring formed through an R¹³ and R¹⁴ radical attached todifferent atoms within the same group, such as in a group having theformula —NR¹⁴C(O)NR¹⁵R¹³, —NR¹³C(NCN)NR¹⁵R¹⁴,—NR¹³(CR¹³R¹⁴)_(q)-heteroaryl or —NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl.

In certain embodiments, the phrase “R¹³ and R¹⁵ together with the atomto which they are attached form a saturated or partially unsaturatedcycloalkyl or saturated or partially unsaturated heterocyclyl ring”refers to a heterocyclic ring formed through an R¹³ and R¹⁵ radicalattached to different atoms within the same group, such as in a grouphaving the formula —NR¹³C(NCN)NR¹⁵R¹⁴, —NR¹⁵(CR¹³R¹⁴)_(q)-aryl, or—NR¹⁵(CR¹³R¹⁴)_(q)-heterocyclyl.

In certain embodiments, the phrase “any two of R¹⁵, R¹⁶ and R¹⁷ togetherwith the atom to which they are attached form a heterocyclic ring”refers to a heterocyclic ring formed from an R¹⁵ and R¹⁶ radicalattached to the same nitrogen atom, such as in a group having theformula NR¹⁵R¹⁶, SO₂NR¹⁵R¹⁶, C(═O)NR¹⁵R¹⁶, or an R¹⁶ or R¹⁷ radicalattached to the same nitrogen atom, such as in a group having theformula NR¹⁵C(═O)NR¹⁶R¹⁷. In other embodiments the phrase refers to aheterocyclic ring formed from an R¹⁵ and R¹⁶radical attached todifferent atoms on the same group, such as in the group NR¹⁵OR¹⁶,NR¹⁵C(═O)R¹⁶, NR¹⁵C(═NCN)NR¹⁶R¹⁷, or NR¹⁵C(═NCN)R¹⁶.

It is to be understood that in instances where two or more radicals areused in succession to define a substituent attached to a structure, thefirst named radical is considered to be terminal and the last namedradical is considered to be attached to the structure in question. Thus,for example, the radical arylalkyl is attached to the structure inquestion by the alkyl group.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof. Unless indicated otherwise,the description or naming of a particular compound in the specificationand claims is intended to include both individual enantiomers,diastereomers mixtures, racemic or otherwise, thereof. Accordingly, thisinvention also includes all such isomers, including diastereomericmixtures, pure diastereomers and pure enantiomers of the compounds ofthis invention.

The term “enantiomer” refers to two stereoisomers of a compound whichare non-superimposable mirror images of one another. The term“diastereomer” refers to a pair of optical isomers which are not mirrorimages of one another. Diastereomers have different physical properties,e.g. melting points, boiling points, spectral properties, andreactivities.

The compounds of the present invention may also exist in differenttautomeric forms, and all such forms are embraced within the scope ofthe invention. The term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomerizations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

In the structures shown herein, where the stereochemistry of anyparticular chiral atom is not specified, then all stereoisomers arecontemplated and included as the compounds of the invention. Wherestereochemistry is specified by a solid wedge or dashed linerepresenting a particular configuration, then that stereoisomer is sospecified and defined.

In addition to compounds of Formula I, the invention also includessolvates, pharmaceutically acceptable prodrugs, and pharmaceuticallyacceptable salts of such compounds.

The phrase “pharmaceutically acceptable” indicates that the substance orcomposition is compatible chemically and/or toxicologically, with theother ingredients comprising a formulation, and/or the mammal beingtreated therewith.

A “solvate” refers to an association or complex of one or more solventmolecules and a compound of the invention. Examples of solvents thatform solvates include, but are not limited to, water, isopropanol,ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine.The term “hydrate” refers to the complex where the solvent molecule iswater.

A “pharmaceutically acceptable prodrug” is a compound that may beconverted under physiological conditions or by solvolysis to thespecified compound or to a pharmaceutically acceptable salt of suchcompound. Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of a compound of the presentinvention. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes phosphoserine, phosphothreonine,phosphotyrosine, 4-hydroxyproline, hydroxylysine, demosine, isodemosine,gamma-carboxyglutamate, hippuric acid, octahydroindole-2-carboxylicacid, statine, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid,penicillamine, ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, cirtulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine. phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.Particular examples of prodrugs of this invention include compounds ofFormula I covalently joined to a phosphate residue or a valine residue.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of Formula I can be derivatized as an amideor alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups may be derivatized as prodrugs byconverting the hydroxy group into groups such as, but not limited to,phosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl groups, as outlined in Advanced DrugDelivery Reviews, 1996, 19, 115. Carbamate prodrugs of hydroxy and aminogroups are also included, as are carbonate prodrugs, sulfonate estersand sulfate esters of hydroxy groups. Derivatization of hydroxy groupsas (acyloxy)methyl and (acyloxy)ethyl ethers wherein the acyl group maybe an alkyl ester, optionally substituted with groups including, but notlimited to, ether, amine and carboxylic acid functionalities, or wherethe acyl group is an amino acid ester as described above, are alsoencompassed. Prodrugs of this type are described in J. Med Chem., 1996,39, 10. More specific examples include replacement of the hydrogen atomof the alcohol group with a group such as (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyloxymethyl, N-(C₁-C₆)alkoxycarbonylaminomethyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₆)alkanoyl, arylacyl andα-aminoacyl, or αaminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids,P(O)OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting fromthe removal of a hydroxyl group of the hemiacetal form of acarbohydrate).

Free amines of compounds of Formula I can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including, but not limited to, ether, amine andcarboxylic acid functionalities. For example, a prodrug can be formed bythe replacement of a hydrogen atom in the amine group with a group suchas R-carbonyl, RO-carbonyl, NRR′-carbonyl where R and R′ are eachindependently (C₁-C₁₀)alkyl, (C₃-C₇)cycloalkyl, benzyl, or R-carbonyl isa natural α-aminoacyl or natural α-aminoacyl-natural α-aminoacyl,—C(OH)C(O)OY wherein Y is H, (C₁-C₆)alkyl or benzyl, —C(OY₀)Y₁ whereinY₀ is (C₁-C₄) alkyl and Y₁ is (C₁-C₆)alkyl, carboxy(C₁-C₆)alkyl,amino(C₁-C₄)alkyl or mono-N- or di-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y₂)Y₃wherein Y₂ is H or methyl and Y₃ is mono-N- or di-N,N-(C₁-C₆)alkylamino,morpholino, piperidin-1-yl or pyrrolidin-1-yl.

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

A “pharmaceutically acceptable salt,” unless otherwise indicated,includes salts that retain the biological effectiveness of the freeacids and bases of the specified compound and that are not biologicallyor otherwise undesirable. A compound of the invention may possess asufficiently acidic, a sufficiently basic, or both functional groups,and accordingly react with any of a number of inorganic or organic basesor acids to form a pharmaceutically acceptable salt. Examples ofpharmaceutically acceptable salts include those salts prepared byreaction of the compounds of the present invention with a mineral ororganic acid or an inorganic base, such salts including sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyn-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycollates, tartrates,methanesulfonates, propanesulfonates. naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates. Since a single compound of thepresent invention may include more than one acidic or basic moiety, thecompounds of the present invention may include mono, di or tri-salts ina single compound.

If the inventive compound is a base, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method available in theart, for example, treatment of the free base with an acidic compound,for example an inorganic acid such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid and the like, or withan organic acid, such as acetic acid, maleic acid, succinic acid,mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid,glycolic acid, salicylic acid, a pyranosidyl acid such as glucuronicacid or galacturonic acid, an alpha hydroxy acid such as citric acid ortartaric acid, an amino acid such as aspartic acid or glutamic acid, anaromatic acid such as benzoic acid or cinnamic acid, a sulfonic acidsuch as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

If the inventive compound is an acid, the desired pharmaceuticallyacceptable salt may be prepared by any suitable method, for example,treatment of the free acid with an inorganic or organic base. Examplesof suitable inorganic salts include those formed with alkali andalkaline earth metals such as lithium, sodium, potassium, barium andcalcium. Examples of suitable organic base salts include, for example,ammonium, dibenzylammonium, benzylammonium, 2-hydroxyethylammonium,bis(2-hydroxyethyl)ammonium, phenylethylbenzylamine,dibenzylethylenediamine, and the like salts. Other salts of acidicmoieties may include, for example, those salts formed with procaine,quinine and N-methylglucosamine, plus salts formed with basic aminoacids such as glycine, ornithine, histidine, phenylglycine, lysine andarginine.

The compounds of Formula I also include other salts of such compoundswhich are not necessarily pharmaceutically acceptable salts, and whichmay be useful as intermediates for preparing and/or purifying compoundsof Formula I and/or for separating enantiomers of compounds of FormulaI.

The present invention also embraces isotopically-labeled compounds ofthe present invention which are identical to those recited herein, butfor the fact that one or more atoms are replaced by an atom having anatomic mass or mass number different from the atomic mass or mass numberusually found in nature. All isotopes of any particular atom or elementas specified is contemplated within the scope of the compounds of theinvention, and their uses. Exemplary isotopes that can be incorporatedinto compounds of the invention include isotopes of hydrogen, carbon,nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine,such as ²H, ³, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S,¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I. Certain isotopically-labeled compounds of thepresent invention (e.g., those labeled with ³H and ¹⁴C) are useful incompound and/or substrate tissue distribution assays. Tritiated (i.e.,³H) and carbon-14 (i.e., ¹⁴C) isotopes are useful for their ease ofpreparation and detectability. Further, substitution with heavierisotopes such as deuterium (i.e., ²H) may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Positron emitting isotopes such as ¹⁵O,¹³N, ¹¹C and ¹⁸F are useful for positron emission tomography (PET)studies to examine substrate receptor occupancy. Isotopically labeledcompounds of the present invention can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes and/orin the Examples herein below, by substituting an isotopically labeledreagent for a non-isotopically labeled reagent.

Metabolites of Compounds of Formula I

Also failing within the scope of this invention are the in vivometabolic products of compounds of Formula I described herein. A“metabolite” is a pharmacologically active product produced throughmetabolism in the body of a specified compound or salt thereof. Suchproducts may result, for example, from the oxidation, reduction,hydrolysis, amidation, deamidation, esterification, deesterification,glucoronidation, enzymatic cleavage, and the like, of the administeredcompound. Accordingly, the invention includes metabolites of compoundsof Formula I, including compounds produced by a process comprisingcontacting a compound of this invention with a mammal for a period oftime sufficient to yield a metabolic product thereof.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto a human, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Synthesis of Compounds of Formula I

Compounds of Formula I may be synthesized by synthetic routes thatinclude processes analogous to those well known in the chemical arts,particularly in light of the description contained herein. The startingmaterials are generally available from commercial sources such asAldrich Chemicals (Milwaukee, Wis.) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared bymethods generally described in Louis F. Fieser and Mary Fieser, Reagentsfor Organic Synthesis, v. 1-19, Wiley, N.Y. (1967-1999 ed.), orBeilsteins Handbuch der organischem Chemie, 4, Aufl. ed.Springer-Verlag, Berlin, including supplements (also available via theBeilstein online database).

Compounds of Formula I may be prepared singly or as compound librariescomprising at least 2, for example 5 to 1,000 compounds, or 10 to 100compounds. Libraries of compounds of Formula I may be prepared by acombinatorial ‘split and mix’ approach or by multiple parallel synthesesusing either solution phase or solid phase chemistry, by proceduresknown to those skilled in the art. Thus according to a further aspect ofthe invention there is provided a compound library comprising at least 2compounds, or pharmaceutically acceptable salts thereof.

For illustrative purposes, Schemes 1-7 show general method for preparingthe compounds of the present invention as well as key intermediates. Fora more detailed description of the individual reaction steps, see theExamples section below. Those skilled in the art will appreciate thatother synthetic routes may be used to synthesize the inventivecompounds. Although specific starting materials and reagents aredepicted in the Schemes and discussed below, other starting materialsand reagents can be easily substituted to provide a variety ofderivatives and/or reaction conditions. In addition, many of thecompounds prepared by the methods described below can be furthermodified in light of this disclosure using conventional chemistry wellknown to those skilled in the art.

Scheme I illustrates synthesis of “N-linked” quinazoline compounds (4)of the present invention wherein A and E are as defined herein.According to Scheme 1, 4-anilino-6-nitro-quinazoline (3) can be preparedby reacting an appropriate aniline (2) with a quinazoline (1)substituted in the 4 position with a suitable leaving group, for examplea chloride, under standard coupling conditions. The coupling reactioncan be performed in a variety of solvents, such as tBuOH, IPA or DCE andmay require elevated temperatures and may require a mild base, such asEtN(iPr)₂. In one example, the reaction is achieved in a mixture of IPAand DCE heated to 80° C. Reduction of the nitro group of compound (3)can be accomplished by a variety of standard reduction protocols knownin the art, such as Pd/C and H₂, Pd/C and hydrazine, Pt/C with NaOH andH₂, Zn/AcOH, Zn/NH₄Cl or Fe/HOAc. In one example, the reduction isaccomplished with Pd/C and H₂. When R² is a halogen, the reduction canbe accomplished Pt/C with NaOH and H₂ or Zn/NH₄Cl. The resulting anilinecan be coupled with halides, or reacted with other suitableelectrophiles such as aldehydes, acid chlorides, etc. to providecompound (4). These reactions may require a suitable base and/orelevated temperatures.

Scheme 2 illustrates an alternative route towards “N-linked” quinazolinecompounds (4) wherein A and E are as defined herein. According to Scheme2, 4-chloro-6-iodoquinazoline (5) can be used in place of4-chloro-6-nitroquinazoline (1) in Scheme 1 to prepare4-anilino-6-iodoquinazoline (6). The palladium mediated cross-couplingreaction of the resulting iodoquinazoline (6) with a suitable amineR¹⁵NH₂ to give compound 4 can be accomplished by treatment with apalladium catalyst, for example Pd(OAc)₂, Pd(PPh₃)₄, PdCl₂(dppf)₂,Pd_(w)(dba)₃, a phosphine ligand and a base in a suitable organicsolvent such as THF, DME or toluene. In one example, the couplingreaction is accomplished using Pd₂(dba)₃, X-PHOS and Cs₂CO₃ in THF andheating to 65° C. Scheme 2 also demonstrates the preparation of C-linkedcompounds (7). These analogs can be prepared from compound (6) bypalladium mediated cross-coupling reactions with boronic acids or organotin compounds using standard Suzuki or Stille reaction conditions wellknown in the art.

Scheme 3 illustrates a route towards “N-linked” oxazoline-quinazolinecompounds wherein A and E are as defined herein. According to Scheme 3,amidine (8) can be condensed with suitable aniline (2) in the presenceof an acid such as HOAc in a suitable organic solvent such as isopropylacetate (IPAc) to provide the thiourea (9). The oxazoline (10) can beprepared by cyclizing the thiourea (9) under a variety of conditions,for example, by treating the thiourea (9) with TsCl and aqueous NaOH inTHF.

Scheme 4 illustrates the synthesis of an ether linked quinazoline (13)of the present invention wherein A and E are as defined herein.According to Scheme 4, 4-chloro-6-oxy-quinazoline (11) can be reactedwith suitable aniline (2) under standard coupling conditions asdescribed in Scheme 1 to provide compound (12). The oxygen moiety ofcompound (11) can be substituted with various R^(a) groups, whereinR^(a) is H, R¹⁵ or a suitable alcohol protecting group, such as an acylgroup. After reaction with the aniline, the optional protection groupcan be removed under suitable conditions, such as ammonia in MeOH incase of an acetate protecting group. The hydroxyl group of compound (12)can be coupled with a suitable alkylhalide R¹⁵—X and an appropriatebase, such as K₂CO₃, Cs₂CO₃ or Cs(OH)₂ in an organic solvent such as DMFor acetone to provide compound 13. In one example, the alkylation isachieved with R¹⁵—Br using Cs₂CO₃ as a base in DMF. Alternatively,R¹⁵—OH can be used in place of R¹⁵—X if the alcohol has been convertedto an activated leaving group, such as a tosylate. In yet anothermethod, the hydroxyl group of 12 can be coupled with an alcohol R¹⁵—OHunder standard Mitsunobu conditions, such as DIAD/PPh₃ in THF, toprovide compound 13.

Scheme 5 illustrates a method of preparing aniline intermediates (2a)and (2b) suitable for use in Schemes 1-4, from phenols (14) and (15),respectively. Phenols (14) and (15) are commercially available or knownin the literature, or can be prepared by those skilled in the art bystandard procedures. Phenol (14) can be reacted with an optionallysubstituted 4-fluoronitrobenzene (16) and a suitable base, for exampleK₂CO₃, NaH, or Cs₂CO₃ in a polar organic solvent such as DMF at elevatedtemperatures to provide the coupled product (17). In one example, phenol(14) is reacted with an optionally substituted 4-fluoronitrobenzene (16)in the presence of Cs₂CO₃ in DMF at 80° C. The nitro group of compound(17) can be reduced to the desired aniline compound (2a) using standardreduction methods such as Pd/C and H₂, Pd/C and hydrazine, Pt/C withNaOH and H₂, Zn/AcOH, ZnNH₄Cl or Fe/HOAc. In one example, the reductionis accomplished with Pd/C and H₂ (40 psi). When R₂ is a halogen, thereduction can be accomplished with Pt/C with NaOH with H₂ or Zn/NH₄Cl.In a similar manner, compound (2b) can be prepared from phenol (15).

Scheme 6 illustrates a method of preparing phenol intermediate (14a)suitable for use in Scheme 5. Chloro-pyridine (18) can be reacted withhydrazine, for example in pyridine at 80° C. The resulting compound canthen be reacted with a carboxylic acid equivalent, such as triethylorthoformate or trimethoxy methane and acid, such as HCl, HOAc or4-methylbenzenesulfonic acid. In one example, the cyclization isachieved with trimethoxy methane and 4-methylbenzenesulfonic acid tofurnish the triazole. The benzyl group can be removed under standardconditions, for example, Pd/C and H₂, to give (14a).

Scheme 7 illustrates a method of preparing phenol intermediate (14b)suitable for use in Scheme 5. A suitably substituted acetal can reactedwith DMF and POCl₃ to provide a dimethylamino-acrylaldehydeintermediate. Conversion of this intermediate to a pyrrazolo-pyrimidinecan be accomplished by treatment with an optionally substituted1H-pyrazol-3-amine in base at elevated temperatures, for example NaOMein MeOH at 60° C. The benzyl group can be removed to give (14b) understandard conditions, such as Pd/C and H₂.

Scheme 8 illustrates the preparation of aniline intermediates (2c) and(2d) suitable for use in Schemes 1-4. According to Scheme 8, thepalladium mediated cross-coupling reaction of2-chloro-4-benzyloxy-pyridine (18) with a suitable amine to givecompound (19) can be accomplished by treatment with a palladiumcatalyst, for example Pd(OAc)₂, Pd(PPh₃)₄, PdCl₂(dppf)₂, Pd₂(dba)₃, aphosphine ligand and a base in a suitable organic solvent such as THF,DME or toluene. In one example, the coupling is accomplished using LHMDSwith Pd₂(dba)₃, X-PHOS and Cs₂CO₃ in THF and heating to 65° C. Theresulting 2-aminopyridine can be optionally protected as theBoc-carbamate under standard conditions, for example Boc₂O in tBuOH. Thebenzyl group of compound (19) can be removed under standard conditions,such as Pd/C and H₂. The resulting phenol is then reacted with anoptionally substituted 4-fluoro-nitrobenzene (16) as described in Scheme5 to provide the coupled product (20). The Boc group of compound (20)can be removed with acid, for example TFA in DCM. The deprotected2-aminopyridine (21) can be converted to an imidazopyridine derivativeby reaction with a suitably substituted 2-halo-carbonyl compound. Forexample, compound (21) can be reacted with either chloroacetaldehyde,chloroacetone, or 2-chloropropanal in THF heated to reflux. Conversionof compound (21) into triazolopyridines can be achieved by two-stepprocedure that includes condensation of (21) with dimethylforamidedimethylacetal to provide a N,N-dimethyl-formimidamide derivative, whichis then reacted with hydroxylamine sulfonic acid to provide thetriazolopyridine. Reduction of the corresponding nitro group can beaccomplished as described in Scheme 5 to provide compounds (2c) and(2d).

Scheme 9 illustrates an alternative synthesis of intermediate anilinecompound (2e) and (2f) suitable for use in Schemes 1-4. According toScheme 9, 2-chloro-5-hydroxypyridine is reacted with an optionallysubstituted 4-fluoronitrobenzene (16) as described in Scheme 5. Thechloro derivative (22) can be converted to the amino derivative (23)under palladium mediated cross coupling conditions as described inScheme 8. Conversion of compound (23) to provide imidazopyridines ortriazolopyridines can be accomplished under suitable conditions asdescribed in Scheme 8. Reduction of the corresponding nitro groups canbe accomplished as described in Scheme 5 to provide compounds (2c) and(2f).

Scheme 10 illustrates an alternative synthesis of intermediate anilinecompound (2g) suitable for use in Schemes 1-4. According to Scheme 10,phenol substituted benzofused-heterocycles (14) and (25) can be reactedwith dimethyl thiocarbamoyl chloride and a base, for example, NaH inTHF, with heating to reflux. Rearrangement of the resulting thiocarbonylcarbamate is accomplished by heating to elevated temperatures, forexample 200° C., in diphenyl ether. The product is then hydrolyzed underbasic conditions, such as KOH in MeOH heated to reflux. The thiol (24)can then be reacted with an optionally substituted 4-fluoronitrobenzene(16) as described in Scheme 5. Reduction of the nitro group can beaccomplished as described in Scheme 5, for example with Fc/HOAc orZn/NH₄Cl, to provide compound (2g). An alternative synthesis of aniline(2g) includes reacting a halo-substituted fused heterocyclic compound(25), where X=Br, with (iPr)₃SiSH and a palladium catalyst, for examplePd(PPh₃)₄ in THF, and healing to reflux. The resulting protected thiol(26) can be de-silated and reacted with an optionally substituted4-fluoronitrobenzene (16) in situ with a fluoride source, such as CsF inDMF. Reduction of the nitro group to yield (2g) is accomplished understandard reaction conditions.

Scheme 11 illustrates a method of preparing aniline (2h) suitable foruse in Schemes 1-4. According to Scheme 11, acid chloride (27) isreacted with 2-pyridone and a base to yield ester (28), for example withEt₃N in DCM. Boronic acid (29) is prepared from the halo substitutedfused heterocycle (25) by standard conditions, for example by treatmentwith nBuLi at low temperatures followed by B(OMe)₃. Compound (28) isthen coupled with boronic acid (29) under palladium mediatedcross-coupling conditions, for example Pd(OAc)₂, PPh₃ and dioxane, andheating to 50° C. (Tatamidani, H.; Kakiuchi, F.; Chatani, N. Org. Lett.2004, 6, 3597). The resulting nitro compound can be reduced understandard conditions as described in Scheme 5, such as Fe/HOAc orZn/NH₄Cl, to provide compound (2h).

Scheme 12 shows a method of preparing compounds of Formula I wherein andA and E are as defined herein, ring B is a fused benzo ring and R³ is aZ group having the formula:

wherein R^(8b) is H or methyl.

Scheme 13 shows a method of preparing compounds of Formula I wherein andA and E are as defined herein, ring B is a fused benzo ring and R³ is aZ group having the formula:

The compounds of Formula I may be prepared using reaction methods knownin the art or by methods analogous to those known in the art. Thisinvention also provides methods of preparing compounds of Formula I,comprising:

(a) reacting a compound of formula (F1)

with a compound of formula (F2)

in which Z represents a leaving atom or group; or

(b) for a compound of Formula I in which G is N, reacting a compound offormula (F3)

in which R represents a tertiary amino group, for exampledi(1-6C)alkylamino, such as dimethylamino, with a compound of formula(F1); followed if necessary, by converting the compound of Formula Iinto another compound of Formula I having a different R³ group.

More particularly, this invention provides methods of preparingcompounds of Formula I, comprising:

(c) for a compound of Formula I wherein R³ is —NHR^(x) and R^(x) is R¹⁵or —C(O)R¹⁵, and R¹⁵ is as defined for Formula I, reacting acorresponding compound of Formula I wherein R³ is —NH₂ with analkylating agent or an acylating agent R¹⁵—X¹ wherein R¹⁵—X¹ is an acidor reactive derivative thereof (such as R¹⁵(O)Cl) or wherein X¹ is aleaving group such as halogen group, optionally in the presence of abase; or

(d) for a compound of Formula I wherein R³ is —NHR¹⁵ and R¹⁵ is asdefined for Formula I, reacting a corresponding compound of Formula Iwherein R³ is an iodide group with a compound having the formula R¹⁵NH₂in the presence of a palladium catalyst and a phosphine ligand; or

(e) for a compound of Formula I wherein R³ is R¹⁵ and R¹⁵ is as definedfor Formula I, reacting a corresponding compound of Formula I wherein R³is an iodide group with a compound having the formula R¹⁵B(OH)₂ orR¹⁵SnBu₃ in the presence of a palladium catalyst and a phosphine ligand;or

(f) for a compound having the Formula I wherein R³ is OR¹⁵ and R¹⁵ isalkyl, alkenyl, or alkynyl, reacting a corresponding compound of FormulaI wherein R³ is OH with R¹⁵—X² wherein R¹⁵ is alkyl, alkenyl or alkynyland X² is a leaving group, in the presence of a base; or

(g) for a compound having the Formula I wherein R³ is OR¹⁵ and R¹⁵ isalkyl, alkenyl or alkynyl, reacting a corresponding compound of FormulaI wherein R³ is —OR^(15a) and —OR^(15a) is a sulfate group such as atosylate group, with a compound having the formula R¹⁵OH in the presenceof a base; or

(h) for a compound having the Formula I wherein R³ is a group of formula(F3)

reacting a corresponding compound of Formula I wherein R³ is an iodidegroup with a compound having the formula (F4)

in the presence of a palladium catalyst, a phosphine ligand and a base;or

(i) for a compound having the Formula I wherein R³ is a group of Formula(F5)

wherein R⁶ is methyl, cyclizing a corresponding compound of Formula Iwherein R³ is a group of Formula (F6)

wherein R⁶ is methyl in the presence of a base and a sulfonyl chloridesuch as tosyl chloride: or

(j) for a compound having the Formula I wherein R³ is a group of Formula(F5)

wherein R⁶ is H, cyclizing corresponding compound of Formula I whereinR³ is a group of the formula (F6) wherein R⁶ is H in the presence ofdiispropyl azodicarboxylate and a phosphine ligand such as PPH₃; or

(k) for a compound having the Formula I wherein R³ is a group of formula(F7)

wherein R⁶ is H, reacting a corresponding compound having the Formula Iwherein R³ is a group of formula (F6) and R⁶ is H in the presence of abase and a sulfonyl chloride.

Certain of the intermediates described in the above described Schemesand in the Examples are believed to be novel and are provided as furtheraspects of the invention. In particular, this invention further providescompound of formula (F1)

wherein R¹, R², A, E and n are as defined for Formula I. Compounds ofFormula (F1) are useful for preparing pharmaceutical compounds such asthe ErbB inhibitors of Formula I.

In preparing compounds of Formula I, protection of remotefunctionalities (e.g., primary or secondary amines, alcohols, etc.) ofintermediates may be necessary. The need for such protection will varydepending on the nature of the remote functionality and the conditionsof the preparation methods. Suitable amino-protecting groups (NH-Pg)include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC),benzyloxycarbonyl (CBz) and 9-fluorenylmethyleneoxycarbonyl (Fmoc). Theneed for such protection is readily determined by one skilled in theart. For a general description of protecting groups and their use, seeT. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons,New York, 1991.

Methods of Separation

In any of the synthetic methods for preparing compounds of Formula I, itmay be advantageous to separate reaction products from one anotherand/or from starting materials. The desired products of each step orseries of steps is separated and/or purified to the desired degree ofhomogeneity by the techniques common in the art. Such separationsinvolve, for example, multiphase extraction, crystallization from asolvent or solvent mixture, distillation, sublimation, orchromatography. Chromatography can involve any number of methodsincluding, for example: reverse-phase and normal phase; size exclusion;ion exchange; high, medium and low pressure liquid chromatographymethods and apparatus; small scale analytical; simulated moving bed(SMB) and preparative thin or thick layer chromatography, as well astechniques of small scale thin layer and flash chromatography.

Another class of separation methods involves treatment of a reactionmixture with a reagent selected to bind to or render otherwise separablea desired product, unreacted starting material, reaction by-product, orthe like. Such reagents include adsorbents such as activated carbon,molecular sieves, ion exchange media, or the like. Alternatively, thereagents can be acids in the case of a basic material, bases in the caseof an acidic material, binding reagents such as antibodies, bindingproteins, selective chelators such as crown ethers, liquid/liquid ionextraction reagents (LIX), or the like.

Selection of appropriate method(s) of separation depends on the natureof the materials involved. For example, boiling point and molecularweight in distillation and sublimation, presence or absence of polarfunctional groups in chromatography, stability of materials in acidicand basic media in multiphase extraction, and the like. One skilled inthe art will apply techniques most likely to achieve the desiredseparation.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereoisomers to the corresponding pure enantiomers. Also,some of the compounds of the present invention may be atropisomers(e.g., substituted biaryls) and are considered as part of thisinvention. Enantiomers can also be separated by use of a chiral HPLCcolumn.

A single stereoisomer, e.g., an enantiomer, substantially free of itsstereoisomer may be obtained by resolution of the racemic mixture usinga method such as formation of diastereomers using optically activeresolving agents (Eliel, E. and Wilen, S. “Stereochemistry of OrganicCompounds,” John Wiley & Sons, Inc., New York. 1994; Lochmuller, C. H.,J. Chromatogr., (1975) 113(3):283-302). Racemic mixtures of chiralcompounds of the invention can be separated and isolated by any suitablemethod, including: (1) formation of ionic, diastereomeric salts withchiral compounds and separation by fractional crystallization or othermethods, (2) formation of diastereomeric compounds with chiralderivatizing reagents, separation of the diastereomers, and conversionto the pure stereoisomers, and (3) separation of the substantially pureor enriched stereoisomers directly under chiral conditions. See: “DrugStereochemistry, Analytical Methods and Pharmacology,” Irving W. Wainer,Ed., Marcel Dekker, Inc., New York (1993).

Under method (1), diastereomeric salts can be formed by reaction ofenantiomerically pure chiral bases such as brucine, quinine, ephedrine,strychnine, α-methyl-β-phenylethylamine (amphetamine), and the like withasymmetric compounds bearing acidic functionality, such as carboxylicacid and sulfonic acid. The diastereomeric salts may be induced toseparate by fractional crystallization or ionic chromatography. Forseparation of the optical isomers of amino compounds, addition of chiralcarboxylic or sulfonic acids, such as camphorsulfonic acid, tartaricacid, mandelic acid, or lactic acid can result in formation of thediastereomeric salts.

Alternatively, by method (2), the substrate to be resolved is reactedwith one enantiomer of a chiral compound to form a diastereomeric pair(E. and Wilen, S. “Stereochemistry of Organic Compounds”, John Wiley &Sons, Inc., 1994, p. 322). Diastereomeric compounds can be formed byreacting asymmetric compounds with enantiomerically pure chiralderivatizing reagents, such as menthyl derivatives, followed byseparation of the diastereomers and hydrolysis to yield the pure orenriched enantiomer. A method of determining optical purity involvesmaking chiral esters, such as a menthyl ester, e.g., (−)menthylchloroformate in the presence of base, or Mosher ester,α-methoxy-α-(trifluoromethyl)phenyl acetate (Jacob III. J. Org. Chem.,(1982) 47:4165), of the racemic mixture, and analyzing the ¹H NMRspectrum for the presence of the two atropisomeric enantiomers ordiastereomers. Stable diastereomers of atropisomeric compounds can beseparated and isolated by normal- and reverse-phase chromatographyfollowing methods for separation of atropisomeric naphthyl-isoquinolines(WO 96/15111). By method (3), a racemic mixture of two enantiomers canbe separated by chromatography using a chiral stationary phase (“ChiralLiquid Chromatography” (1989) W. J. Lough, Ed., Chapman and Hall, NewYork; Okamoto, J. of Chromatogr., (1990) 513:375-378). Enriched orpurified enantiomers can be distinguished by methods used to distinguishother chiral molecules with asymmetric carbon atoms, such as opticalrotation and circular dichroism.

Methods of Treatment with Compounds of Formula I

The compounds of the present invention can be used as prophylactics ortherapeutic agents for treating diseases mediated by modulation orregulation of type I receptor tyrosine kinases anchor serine, threonine,and/or dual specificity kinases. An “effective amount” is intended tomean that amount of compound that, when administered to a mammal in needof such treatment, is sufficient to effect treatment for a diseasemediated by the activity of one or more type I receptor tyrosine kinasesand/or serine, threonine, and/or dual specificity kinases. Thus, forexample, a therapeutically effective amount of a compound selected fromFormula I or a solvate, metabolite, or pharmaceutically acceptable saltor prodrug thereof, is a quantity sufficient to modulate, regulate, orinhibit the activity of one or more type I receptor tyrosine kinasesand/or serine, threonine, and/or dual specificity kinases such that adisease condition which is mediated by that activity is reduced oralleviated.

The terms “treat” or “treatment” refer to both therapeutic treatment andprophylactic or preventative measures, wherein the object is to preventor slow down (lessen) an undesired physiological change or disorder. Forpurposes of this invention, beneficial or desired clinical resultsinclude, but are not limited to, alleviation of symptoms, diminishmentof extent of disease, stabilized (i.e., not worsening) state of disease,delay or slowing of disease progression, amelioration or palliation ofthe disease state, and remission (whether partial or total), whetherdetectable or undetectable. “Treatment” can also mean prolongingsurvival as compared to expected survival if not receiving treatment.Those in need of treatment include those already with the condition ordisorder as well as those prone to have the condition or disorder orthose in which the condition or disorder is to be prevented. The terms“treating,” “treat,” and “treatment” embrace both preventative, i.e.,prophylactic, and palliative treatment.

The compounds of the present invention possess anti-cell-proliferationproperties, which are believed to arise from their Class I receptortyrosine kinase inhibitory activity. Accordingly the compounds of thepresent invention are expected to be useful in the treatment of diseasesor medical conditions mediated alone or in part by Class I receptortyrosine kinase enzymes, i.e. the compounds may be used to produce aClass I receptor tyrosine kinase inhibitory effect in a warm-bloodedanimal in need of such treatment. Thus the compounds of the presentinvention provide a method for treating the proliferation of malignantcells characterized by inhibition of Class I receptor tyrosine kinaseenzymes, i.e., the compounds may be used to produce ananti-proliferative effect mediated alone or in part by the inhibition ofClass I receptor tyrosine kinase. Accordingly, the compounds of thepresent invention are expected to be useful in the treatment of cancerby providing an anti-proliferative effect, particularly in the treatmentof Class I receptor tyrosine kinase sensitive cancers such as cancers ofthe breast, lung, colon, rectum, stomach, prostate, bladder, pancreasand ovary. The compounds of the present invention are also expected tobe useful in the treatment of other cell-proliferation diseases such aspsoriasis.

Accordingly, one aspect of this invention relates to a pharmaceuticalcomposition for the treatment of a hyperproliferative disorder or anabnormal cell growth in a mammal, which comprises a therapeuticallyeffective amount of a compound of the present invention, or a solvate,metabolite, or pharmaceutically acceptable salt or prodrug thereof, anda pharmaceutically acceptable carrier.

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

“Abnormal cell growth,” as used herein, unless otherwise indicated,refers to cell growth that is independent of normal regulatorymechanisms (e.g., loss of contact inhibition). This includes, forexample, the abnormal growth of: (1) tumor cells (tumors) thatproliferate by expressing a mutated tyrosine kinase or over-expressionof a receptor tyrosine kinase; (2) benign and malignant cells of otherproliferative diseases in which aberrant tyrosine kinase activationoccurs; (3) any tumors that proliferate by receptor tyrosine kinases;(4) any tumors that proliferate by aberrant serine/threonine kinaseactivation; and (5) benign and malignant cells of other proliferativediseases in which aberrant serine/theroine kinase activation occurs.

In one embodiment, abnormal cell growth in cancer. According, thisinvention provides methods of treating cancer, comprising administeringto a mammal in need thereof a therapeutic amount of a composition ofthis invention.

In certain embodiments, said cancer is selected from lung cancer, bonecancer, pancreatic cancer, skin cancer, cancer of the head or neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the cervix, carcinoma of thevagina, carcinoma of the vulva, Hodgkin's Disease, cancer of theesophagus, cancer of the small intestine, cancer of the endocrinesystem, cancer of the thyroid gland, cancer of the parathyroid gland,cancer of the adrenal gland, sarcoma of soft tissue, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, lymphocytic lymphomas, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,neoplasms of the central nervous system (CNS), primary CNS lymphoma,spinal axis tumors, brain stem glioma, pituitary adenoma, or acombination of one or more of the foregoing cancer.

The invention also relates to a pharmaceutical composition for thetreatment of pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) or the treatmentof pain in a mammal, which comprises a therapeutically effective amountof a compound of the present invention, or a solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof, and apharmaceutically acceptable carrier.

The invention also relates to a method for the treatment of pancreatitisor kidney disease or the treatment of pain in a mammal as describedabove, which comprises administering to said mammal a therapeuticallyeffective amount of a compound of the present invention, or a solvate,metabolite, or pharmaceutically acceptable salt or prodrug thereof incombination with a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for theprevention of blastocyte implantation in a mammal, which comprises atherapeutically effective amount of a compound of the present invention,or a solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof, and a pharmaceutically acceptable carrier.

The invention also relates to a method for the prevention of blastocyteimplantation in a mammal, which comprises administering to said mammal atherapeutically effective amount of a compound of the present invention,or a solvate, metabolite, or pharmaceutically acceptable salt or prodrugthereof in combination with a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treatinga disease related to vasculogenesis or angiogenesis in a mammal, whichcomprises a therapeutically effective amount of a compound of thepresent invention, or a solvate, metabolite, or pharmaceuticallyacceptable salt or prodrug thereof, and a pharmaceutically acceptablecarrier.

The invention also relates to a method for treating a disease related tovasculogenesis or angiogenesis in a mammal, which comprisesadministering to said mammal a therapeutically effective amount of acompound of the present invention, or a solvate, metabolite, orpharmaceutically acceptable salt or prodrug thereof in combination witha pharmaceutically acceptable carrier. Examples of such diseasesinclude, but are not limited to, tumor angiogenesis, chronicinflammatory disease or other inflammatory condition such as rheumatoidarthritis, atherosclerosis, inflammatory bowel disease, skin diseasessuch as psoriasis, eczema, and scleroderma, diabetes, diabeticretinopathy, retinopathy of prematurity, age-related maculardegeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma andovarian, breast, lung, pancreatic, prostate, colon and epidermoidcancer.

The invention also relates to a pharmaceutical composition for treatinga disease or condition related to inflammatory disease, autoimmunedisease, destructive bone disorders, proliferative disorders, infectiousdisease, viral disease, fibrotic disease or neurodegenerative disease ina mammal which comprises a therapeutically effective amount of acompound of the present invention, or a pharmaceutically acceptablesalt, prodrug or hydrate thereof, and a pharmaceutically acceptablecarrier. Examples of the above diseases and/or conditions include but isnot limited to rheumatoid arthritis, atherosclerosis, inflammatory boweldisease, skin diseases such as psoriasis, eczema, and scleroderma,diabetes and diabetic complications, diabetic retinopathy, retinopathyof prematurity, age-related macular degeneration, hemangioma, chronicobstructive pulmonary disease, idiopathic pulmonary fibrosis, allergicresponses including asthma allergic rhinitis and atopic dermatitis,renal disease and renal failure, polycystic kidney disease, acutecoronary syndrome, congestive heart failure, osteoarthritis,neurofibromatosis, organ transplant rejection, cachexia and pain.

Patients that can be treated with compositions of the present inventioninclude, for example, patients that have been diagnosed as havingpsoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer,CMML, pancreatic cancer, skin cancer, cancer of the head and neck,cutaneous or intraocular melanoma, uterine cancer, ovarian cancer,rectal cancer, cancer of the anal region, stomach cancer, colon cancer,breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas,carcinoma of the fallopian tubes, carcinoma of the endometrium,carcinoma of the cervix, carcinoma of the vagina or carcinoma of thevulva), Hodgkin's disease, cancer of the esophagus, cancer of the smallintestine, cancer of the endocrine system (e.g., cancer of the thyroid,parathyroid or adrenal glands), sarcomas of soft tissues, cancer of theurethra, cancer of the penis, prostate cancer, chronic or acuteleukemia, solid tumors of childhood, lymphocytic lymphomas, cancer ofthe bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma,carcinoma of the renal pelvis), or neoplasms of the central nervoussystem (e.g., primary CNS lymphoma, spinal axis tumors, brain stemgliomas or pituitary adenomas).

Further provided is a compound of Formula I for use as a medicament inthe treatment of the diseases and conditions described above in amammal, such as a human, suffering from such disorder. Also provided isthe use of a compound of Formula I in the preparation of a medicamentfor the treatment of the diseases and conditions described above in amammal, such as a human, suffering from such disorder.

Combination Therapy

The compounds of the present invention can be used in combination withone or more additional drugs such as described below. The dose of thesecond drug can be appropriately selected based on a clinically employeddose. The proportion of the compound of the present invention and thesecond drug can be appropriately determined according to theadministration subject, the administration route, the target disease,the clinical condition, the combination, and other factors. In caseswhere the administration subject is a human, for instance, the seconddrug may be used in an amount of 0.01 to 100 parts by weight per part byweight of the compound of the present invention.

In certain embodiment of the invention, a method for the treatment ofabnormal cell growth in a mammal comprises administering to a mammal anamount of a compound of Formula I that is

effective in treating abnormal cell growth in combination with ananti-tumor agent selected from the following categories:

(i) antiproliferative/anti-neoplastic drugs and combinations thereof, asused in medical oncology, such as alkylating agents (for example,cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan,chlorambucil, busulphan and nitrosoureas); anti-metabolites (forexample, antifolates such as such as fluoropyrimidines like5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosinearabinside, hydroxyurea, or, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid); antitumor antibiotics (for example, anthracyclines likeadriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin,mitomycin-C, dactinomycin and mithramycin); antimitotic agents (forexample, vinca alkaloids like vincristine, vinblastine, vindesine andvinorelbine and taxoids like taxol and taxotere); topoisomeraseinhibitors (for example epipodophyllotoxins like eptoposide andteniposide, amsacrine, topotecan and campothecin); and mitotic kinesinKSP inhibitors;

(ii) cytostatic agents such as antiestrogens (for example, tamoxifen,toremifene, raloxifene, droloxifene and iodoxyfene); estrogen receptordown regulators (for example, fulvestratrant); antiandrogens (forexample, bicalutamide, flutamide, nilutamide, cyproxerone acetate andCASODEX™(4′-cyano-3-(4-fluorophenylsulfphonyl)-2-hydroxy-2-methyl-3′-trifluoromethyl)propionanilide));LHRH antagonists or LHRH agonists (for example, goserelin, leuporelinand buserelin); progestogens (for example, megestrol acetate); aromataseinhibitors (for example, asanastrozole, letrozole, vorazole andexemestane); inhibitors of 5α-reductase such as finasteride; and p38inhibitors such as those disclosed in U.S. Publication Nos.2004/0176325, 2004/0180896, and 2004/0192635;

(iii) agents which inhibit cancer cell invasion (for example,metalloproteinase inhibitors like marimastat and inhibitors of urokinaseplasminogne activator receptor function);

(iv) inhibitors of growth factor function such as growth factorantibodies, growth factor receptor antibodies (for example, theanti-erbB2 antibody trastuzumab [HERCEPTIN™] and the anti-erbB1 antibodycetuximab [C225]), farnesyl transferase inhibitors, tyrosine kinaseinhibitors and serine-threonine kinase inhibitors (for example,inhibitors of the epidermal growth factor family tyrosine kinases suchasN-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine(gefitinib, AZD1839),N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine(erlotinib, OSI-774) and6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)quinazolin-4-amine(Cl 1033)); inhibitors of the platelet-derived growth factor family;inhibitors of the hepatocytc growth factor family; and MEK inhibitorssuch as PD325901 and compounds such as those disclosed in U.S. PatentPublication 2004/0116710;

(v) antiangiogenic agents such as those which inhibit the effects ofvascular endothelial growth factor (for example, the anti-vascularendothelial cell growth factor antibody bevacizumab [AVASTIN™],compounds such as those disclosed in PCT Publication Nos. WO 97/22596,WO 97/30035, WO 97/32856, and WO 98/13354) and compounds that work byother mechanisms (for example, linomide, inhibitors of interin αvβ3function, MMP inhibitors, COX-2 inhibitors and angiostatin);

(vi) vascular damaging agents such as Combretastatin A4 and compoundsdisclosed in PCT Publication Nos. WO 99/02166, WO 0/40529, WO 00/41669,WO 01/92224, WO 02/04434, and WO 02/08213;

(vii) antisense therapies (for example, those which are directed to thetargets listed above such as ISIS 2503, and anti-ras antisense);

(viii) gene therapy approaches, including for example GVAX™, approachesto replace aberrant genes such as aberrant p53 or aberrant BRCA1 orBRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such asthose using cytosine deaminase, thymidine kinase or a bacterialnitroreductase enzyme and approaches to increase patient tolerance tochemotherapy or radiotherapy such as multi-drug resistance gene therapy;

(ix) interferon; and

(x) immunotherapy approaches, including for example ex-vivo and in-vivoapproaches to increase the immunogenicity of patient tumor cells, suchas transfection with cytokines such as interleukin 2, interleukin 4 orgranulocyte-macrophage colony stimulating factor, approaches to decreaseT-cell anergy, approaches to using transfected immune cells such ascytokine-transfected dendritic cells, approaches usingcytokine-transfected tumor cell lines and approaches usinganti-idiotypic antibodies.

In one embodiment the second compound of the pharmaceutical combinationformulation or dosing regimen has complementary activities to thecompound of Formula I such that they do not adversely affect each other.Such drugs are suitably present in combination in amounts that areeffective for the purpose intended. Accordingly, another aspect of thepresent invention provides a composition comprising a compound ofFormula I, or a solvate, metabolite, or pharmaceutically acceptable saltor prodrug thereof, in combination with a second drug, such as describedherein.

The compound(s) of Formula I and the additional pharmaceutically activeagent(s) may be administered together in a unitary pharmaceuticalcomposition or separately and, when administered separately this mayoccur simultaneously or sequentially in any order. Such sequentialadministration may be close in time or remote in time. The amounts ofthe compound(s) of Formula I and the second agent(s) and the relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

Suitable dosages for any of the above coadministered agents are thosepresently used and may be lowered due to the combined action (synergy)of the newly identified agent and other chemotherapeutic agents ortreatments.

The combination therapy may provide “synergy” and prove “synergistic”,i.e., the effect achieved when the active ingredients used together isgreater than the sum of the effects that results from using thecompounds separately. A synergistic effect may be attained when theactive ingredients are: (1) co-formulated and administered or deliveredsimultaneously in a combined, unit dosage formulation; (2) delivered byalternation or in parallel as separate formulations; or (3) by someother regimen. When delivered in alternation therapy, a synergisticeffect may be attained when the compounds are administered or deliveredsequentially, e.g., by different injections in separate syringes. Ingeneral, during alternation therapy, an effective dosage of each activeingredient is administered sequentially, i.e., serially, whereas incombination therapy, effective dosages of two or more active ingredientsare administered together.

The compounds of the present invention can be used, for example incombination with additional drug(s) such as a therapeutic agent for

Administration of Compounds of Formula I

The compounds of the invention may be administered by any routeappropriate to the condition to be treated. Suitable routes includeoral, parenteral (including subcutaneous, intramuscular, intravenous,intraarterial, intradermal, intrathecal and epidural), transdermal,rectal, nasal, topical (including buccal and sublingual), vaginal,intraperitoneal, intrapulmonary and intranasal. It will be appreciatedthat the preferred route may vary with for example the condition of therecipient. Where the compound is administered orally, it may beformulated as a pill, capsule, tablet, etc. with a pharmaceuticallyacceptable carrier or excipient. Where the compound is administeredparenterally, it may be formulated with a pharmaceutically acceptableparenteral vehicle and in a unit dosage injectable form, as detailedbelow.

Pharmaceutical Formulations

In order to use a compound of Formula I or a pharmaceutically acceptablesalt, solvate, metabolite or prodrug thereof for the therapeutictreatment (including prophylactic treatment) of mammals includinghumans, it is normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. According tothis aspect of the invention there is provided a pharmaceuticalcomposition that comprises a compound of the Formula I, or apharmaceutically acceptable salt, solvate, metabolite or prodrugthereof, in association with a pharmaceutically acceptable diluent orcarrier.

The pharmaceutical compositions of the invention are formulated, dosedand administered in a fashion, i.e., amounts, concentrations, schedules,course, vehicles and route of administration, consistent with goodmedical practice. Factors for consideration in this context include theparticular disorder being treated, the particular mammal being treated,the clinical condition of the individual patient, the cause of thedisorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. The therapeutically effective amount ofthe compound to be administered will be governed by such considerations,and is the minimum amount necessary to prevent, ameliorate, or treat thedisorder. The compound of the present invention is typically formulatedinto pharmaceutical dosage forms to provide an easily controllabledosage of the drug and to enable patient compliance with the prescribedregimen.

The composition for use herein is preferably sterile. In particular,formulations to be used for in vivo administration must be sterile. Suchsterilization is readily accomplished, for example, by filtrationthrough sterile filtration membranes. The compound ordinarily can bestored as a solid composition, a lyophilized formulation or as anaqueous solution.

Pharmaceutical formulations of the compounds of the present inventionmay be prepared for various routes and types of administration. Forexample, a compound of Formula I having the desired degree of purity mayoptionally be mixed with pharmaceutically acceptable diluents, carriers,excipients or stabilizers (Remington's Pharmaceutical Sciences (1980)16th edition, Osol, A. Ed.), in the form of a lyophilized formulation, amilled powder, or an aqueous solution. Formulation may be conducted bymixing at ambient temperature at the appropriate pH, and at the desireddegree of purity, with physiologically acceptable carriers, i.e.,carriers that are non-toxic to recipients at the dosages andconcentrations employed. The pH of the formulation depends mainly on theparticular use and the concentration of compound, but may range fromabout 3 to about 8. Formulation in an acetate buffer at pH 5 is asuitable embodiment. The formulations may be prepared using conventionaldissolution and mixing procedures. For example, the bulk drug substance(i.e., compound of the present invention or stabilized form of thecompound (e.g., complex with a cyclodextrin derivative or other knowncomplexation agent) is dissolved in a suitable solvent in the presenceof one or more excipients.

The particular carrier, diluent or excipient used will depend upon themeans and purpose for which the compound of the present invention isbeing applied. Solvents are generally selected based on solventsrecognized by persons skilled in the art as safe (GRAS) to beadministered to a mammal. In general, safe solvents are non-toxicaqueous solvents such as water and other non-toxic solvents that aresoluble or miscible in water. Suitable aqueous solvents include water,ethanol, propylene glycol, polyethylene glycols (e.g., PEG 400, PEG300), etc. and mixtures thereof. Acceptable diluents, carriers,excipients and stabilizers are nontoxic to recipients at the dosages andconcentrations employed, and include buffers such as phosphate, citrateand other organic acids; antioxidants including ascorbic acid andmethionine; preservatives (such as octadecyldimethylbenzyl ammoniumchloride; hexamethonium chloride; benzalkonium chloride, benzethoniumchloride; phenol, butyl or benzyl alcohol; alkyl parabens such as methylor propyl paraben; catechol; resorcinol; cyclohexanol; 3-pentanol; andm-cresol); low molecular weight (less than about 10 residues)polypeptides; proteins, such as serum albumin, gelatin, orimmunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;amino acids such as glycine, glutamine, asparagine, histidine, arginine,or lysine; monosaccharides, disaccharides and other carbohydratesincluding glucose, mannose, or dextrins; chelating agents such as EDTA;sugars such as sucrose, mannitol, trehalose or sorbitol; salt-formingcounter-ions such as sodium; metal complexes (e.g., Zn-proteincomplexes); and/or non-ionic surfactants such as TWEEN™, PLURONICS™ orpolyethylene glycol (PEG). The formulations may also include one or morestabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament). The active pharmaceuticalingredients may also be entrapped in microcapsules prepared, forexample, by coacervation techniques or by interfacial polymerization,for example, hydroxymethylcellulose or gelatin-microcapsules andpoly(methylmethacylate) microcapsules, respectively, in colloidal drugdelivery systems (for example, liposomes, albumin microspheres,microemulsions, nano-particles and nanocapsules) or in macroemulsions.Such techniques are disclosed in Remington's Pharmaceutical Sciences16th edition, Osol, A. Ed. (1980). A “liposome” is a small vesiclecomposed of various types of lipids, phospholipids and/or surfactantwhich is useful for delivery of a drug (such as the compounds disclosedherein and, optionally, a chemotherapeutic agent) to a mammal. Thecomponents of the liposome are commonly arranged in a bilayer formation,similar to the lipid arrangement of biological membranes.

Sustained-release preparations of compounds of Formula I may beprepared. Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of Formula I, which matrices are in the form of shapedarticles, e.g., films, or microcapsules. Examples of sustained-releasematrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate,degradable lactic acid-glycolic acid copolymers such as the LUPRONDEPOT™ (injectable microspheres composed of lactic acid-glycolic acidcopolymer and leuprolide acetate) and poly-D-(−)-3-hydroxybutyric acid.

The pharmaceutical compositions of compounds of Formula I may be in theform of a sterile injectable preparation, such as a sterile injectableaqueous or oleaginous suspension. This suspension may be formulatedaccording to the known art using those suitable dispersing or wettingagents and suspending agents which have been mentioned above. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a non-toxic parenterally acceptable diluent or solvent,such as a solution in 1,3-butanediol or prepared as a lyophilizedpowder. Among the acceptable vehicles and solvents that may be employedare water, Ringer's solution and isotonic sodium chloride solution. Inaddition, sterile fixed oils may conventionally be employed as a solventor suspending medium. For this purpose any bland fixed oil may beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid may likewise be used in the preparation ofinjectables.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents.

The compositions of the invention may also be in a form suitable fororal use (for example as tablets, lozenges, hard or soft capsules,aqueous or oily suspensions, emulsions, dispersible powders or granules,syrups or elixirs), for topical use (for example as creams, ointments,gels, or aqueous or oily solutions or suspensions), for administrationby inhalation (for example as a finely divided powder or a liquidaerosol), for administration by insufflation (for example as a finelydivided powder)

Suitable pharmaceutically-acceptable excipients for a tablet formulationinclude, for example, inert diluents such as lactose, sodium carbonate,calcium phosphate or calcium carbonate, granulating and disintegratingagents such as corn starch or algenic acid, binding agents such asstarch; lubricating agents such as magnesium stearate, stearic acid ortalc; preservative agents such as ethyl or propyl p-hydroxybenzoate. andanti-oxidants, such as ascorbic acid. Tablet formulations may beuncoated or coated either to modify their disintegration and thesubsequent absorption of the active ingredient within thegastrointestinal tract, or to improve their stability and/or appearance,in either case using conventional coating agents and procedures wellknown in the art.

Compositions for oral use may be in the form of hard gelatin capsules inwhich the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules in which the active ingredient is mixed with water oran oil such as peanut oil, liquid paraffin, or olive oil.

Aqueous suspensions generally contain the active ingredient in finelypowdered form together with one or more suspending agents, such assodium carboxymethylcellulose, methylcellulose,hydroxypropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone,gum tragacanth and gum acacia; dispersing or wetting agents such aslecithin or condensation products of an alkylene oxide with fatty acids(for example polyoxethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols, for exampleheptadecaethyleneoxyoctanol, or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol such aspolyoxyethylene sorbitol monooleate, or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides, for example polyethylene sorbitan monooleate. The aqueoussuspensions may also contain one or more preservatives (such as ethyl orpropyl p-hydroxybenzoate, anti-oxidants (such as ascorbic acid),coloring agents, flavoring agents, and/or sweetening agents (such assucrose, saccharine or aspartame).

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil (such as arachis oil, olive oil, sesame oil orcoconut oil) or in a mineral oil (such as liquid paraffin). The oilysuspensions may also contain a thickening agent such as beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set outabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water generally contain the activeingredient together with a dispersing or wetting agent, suspending agentand one or more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients such as sweetening, flavoring and coloring agents,may also be present.

The pharmaceutical compositions of the invention may also be in the formof oil-in-water emulsions. The oily phase may be a vegetable oil, suchas olive oil or arachis oil, or a mineral oil, such as for exampleliquid paraffin or a mixture of any of these. Suitable emulsifyingagents may be, for example, naturally-occurring gums such as gum acaciaor gum tragacanth, naturally-occurring phosphatides such as soya bean,lecithin, esters or partial esters derived from fatty acids and hexitolanhydrides (for example sorbitan monooleate) and condensation productsof the said partial esters with ethylene oxide such as polyoxyethylenesorbitan monooleate. The emulsions may also contain sweetening,flavoring and preservative agents.

Syrups and elixirs may be formulated with sweetening agents such asglycerol, propylene glycol, sorbitol, aspartame or sucrose, and may alsocontain a demulcent, preservative, flavoring and/or coloring agent.

Suppository formulations may be prepared by mixing the active ingredientwith a suitable non-irritating excipient that is solid at ordinarytemperatures but liquid at the rectal temperature and will thereforemelt in the rectum to release the drug. Suitable excipients include, forexample, cocoa butter and polyethylene glycols. Formulations suitablefor vaginal administration may be presented as pessaries, tampons,creams, gels, pastes, foams or spray formulations containing in additionto the active ingredient such carriers as are known in the art to beappropriate.

Topical formulations, such as creams, ointments, gels and aqueous oroily solutions or suspensions, may generally be obtained by formulatingan active ingredient with a conventional, topically acceptable, vehicleor diluent using conventional procedures well known in the art.

Compositions for transdermal administration may be in the form of thosetransdermal skin patches that are well known to those of ordinary skillin the art.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration may beprepared according to conventional methods and may be delivered withother therapeutic agents such as compounds heretofore used in thetreatment or prophylaxis disorders as described below.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways depending upon the method used foradministering the drug. For example, an article for distribution caninclude a container having deposited therein the pharmaceuticalformulation in an appropriate form. Suitable containers are well knownto those skilled in the art and include materials such as bottles(plastic and glass), sachets, ampoules, plastic bags, metal cylinders,and the like. The container may also include a tamper-proof assemblageto prevent indiscreet access to the contents of the package. Inaddition, the container has deposited thereon a label that describes thecontents of the container. The label may also include appropriatewarnings. The formulations may also be packaged in unit-dose ormulti-dose containers, for example scaled ampoules and vials, and may bestored in a freeze-dried (lyophilized) condition requiring only theaddition of the sterile liquid carrier, for example water, for injectionimmediately prior to use. Extemporaneous injection solutions andsuspensions are prepared from sterile powders, granules and tablets ofthe kind previously described. Preferred unit dosage formulations arethose containing a daily dose or unit daily sub-dose, as herein aboverecited, or an appropriate fraction thereof, of the active ingredient.

The invention further provides veterinary compositions comprising acompound of Formula I together with a veterinary carrier therefore.Veterinary carriers are materials useful for the purpose ofadministering the composition and may be solid, liquid or gaseousmaterials which are otherwise inert or acceptable in the veterinary artand are compatible with the active ingredient. These veterinarycompositions may be administered parenterally, orally or by any otherdesired route.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. In one embodiment, asuitable amount of a compound of Formula I is administered to a mammalin need thereof. Administration in one embodiment occurs in an amountbetween about 0.001 mg/kg of body weight to about 60 mg/kg of bodyweight per day. In another embodiment, administration occurs in anamount between 0.5 mg/kg of body weight to about 40 mg/kg of body weightper day. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smalldoses for administration throughout the day. For further information onroutes of administration and dosage regimes, see Chapter 25.3 in Volume5 of Comprehensive Medicinal Chemistry (Corwin Hansch: Chairman ofEditorial Board), Pergamon Press 1990, which is specificallyincorporated herein by reference.

The invention further provides veterinary compositions comprising atleast one active ingredient as above defined together with a veterinarycarrier therefore. Veterinary carriers are materials useful for thepurpose of administering the composition and may be solid, liquid orgaseous materials which are otherwise inert or acceptable in theveterinary art and are compatible with the active ingredient. Theseveterinary compositions may be administered parenterally, orally or byany other desired route.

The amount of a compound of this invention that is combined with one ormore excipients to produce a single dosage form will necessarily varydepending upon the subject treated, the severity of the disorder orcondition, the rate of administration, the disposition of the compoundand the discretion of the prescribing physician. In one embodiment, asuitable amount of a compound of Formula I is administered to a mammalin need thereof. Administration in one embodiment occurs in an amountbetween about 0.001 mg/kg of body weight to about 60 mg/kg of bodyweight per day. In another embodiment, administration occurs in anamount between 0.5 mg/kg of body weight to about 40 mg/kg of body weightper day. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger doses may be employed without causing any harmful side effect,provided that such larger doses are first divided into several smalldoses for administration throughout the day. For further information onroutes of administration and dosage regimes, see Chapter 25.3 in Volume5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman ofEditorial Board), Pergamon Press 1990, which is specificallyincorporated herein by reference.

Articles of Manufacture

In another embodiment of the invention, an article of manufacture, or“kit”, containing materials useful for the treatment of the disordersdescribed above is provided. In one embodiment, the kit comprises acontainer comprising a compound of Formula I, or a solvate, metabolite,or pharmaceutically acceptable salt or prodrug thereof. The kit mayfurther comprise a label or package insert on or associated with thecontainer. The term “package insert” is used to refer to instructionscustomarily included in commercial packages of therapeutic products,that contain information about the indications, usage, dosage,administration, contraindications and/or warnings concerning the use ofsuch therapeutic products. In one embodiment, the label or packageinserts indicates that the composition comprising a compound of FormulaI can be used to treat one or more of the diseases or disordersdisclosed herein.

In one embodiment, the kit further comprises a container. Suitablecontainers include, for example, bottles, vials, syringes, blister pack,etc. The container may be formed from a variety of materials such asglass or plastic. The container may hold a compound of Formula I or aformulation thereof which is effective for treating one or more diseasesor disorders disclosed herein and may have a sterile access port (forexample, the container may be an intravenous solution bag or a vialhaving a stopper pierceable by a hypodermic injection needle).

The kit may further comprise directions for the administration of thecompound of Formula I and, if present, the second pharmaceuticalformulation. For example, when the kit comprises a first compositioncomprising a compound of Formula I and a second pharmaceuticalformulation, the kit may further comprise directions for thesimultaneous, sequential or separate administration of the first andsecond pharmaceutical compositions to a patient in need thereof.

In another embodiment, the kits are suitable for the delivery of solidoral forms of a compound of Formula I, such as tablets or capsules. Sucha kit can include a number of unit dosages. Such kits can include a cardhaving the dosages oriented in the order of their intended use. Anexample of such a kit is a “blister pack”. Blister packs are well knownin the packaging industry and are widely used for packagingpharmaceutical unit dosage forms. If desired, a memory aid can beprovided, for example in the form of numbers, letters, or other markingsor with a calendar insert, designating the days in the treatmentschedule in which the dosages can be administered.

According to one embodiment, an article of manufacture may comprise (a)a first container with a compound of Formula I contained therein; andoptionally (b) a second container with a second pharmaceuticalformulation contained therein, wherein the second pharmaceuticalformulation comprises a second compound having, for example,antihyperproliferative activity. Alternatively, or additionally, thearticle of manufacture may further comprise a third container comprisinga pharmaceutically-acceptable buffer, such as bacteriostatic water forinjection (BWFI), phosphate-buffered saline, Ringer's solution anddextrose solution. It may further include other materials desirable froma commercial and user standpoint, including other buffers, diluents,filters, needles, and syringes.

In certain other embodiments wherein the kit comprises a composition ofFormula I and a second therapeutic agent, the kit may comprise acontainer for containing the separate compositions such as a dividedbottle or a divided foil packet, however, the separate compositions mayalso be contained within a single, undivided container. Typically, thekit comprises directions for the administration of the separatecomponents. The kit form is particularly advantageous when the separatecomponents are preferably administered in different dosage forms (e.g.,oral and parenteral), are administered at different dosage intervals, orwhen titration of the individual components of the combination isdesired by the prescribing physician.

BIOLOGICAL EXAMPLES Example A EGFR/ErbB2 Enzymatic Assays

Thermo LabSystems Immulon 4HBX 96-well plates are coated by incubationovernight at room temperature with 100 μL per well of 0.25 mg/mL Poly(Glu, Tyr) 4:1 (PGT) (Sigma Chemical Co., St. Louis, Mo.) in PBS(phosphate buffered saline). Excess PGT is removed by aspiration, andthe plate is washed three times with wash buffer (0.1% Tween 20 in PBS).The kinase reaction is performed in 100 μL of 50 mM HEPES (pH 7.3)containing 125 mM sodium chloride, 24 mM magnesium chloride, 0.1 mMsodium orthovanadate, 15 μM ATP (adenosine triphosphate) and 0.3units/mL. EGFR (epidermal growth factor receptor) (BIOMOL ResearchLaboratories, Inc., Plymouth Meeting, Pa.). The compound in DMSO(dimethylsulfoxide) is added to give a final DMSO concentration of about1%. Phosporylation is initiated by the addition of ATP and incubated for30 minutes at room temperature. The kinase reaction is terminated byaspiration of the reaction mixture and subsequent washing with washbuffer (see above). Phosphorylated PGT is detected by 30 incubation with100 μL per well HRP conjugated PY20 antiphosphotyrosine antibody (ZymedLaboratories, Inc., South San Francisco, Calif.) diluted to 0.2 μg/mL in3% BSA and 0.05% Tween 20 in PBS. Antibody is removed by aspiration, andthe plate is washed with wash buffer. The colorimetric signal isdeveloped by the addition of 100 μL per well TMB Microwell PeroxidaseSubstrate (Kirkegaard and Perry, Gaithersburg, Md.), and stopped by theaddition of 100 μL per well 1M phosphoric acid. Phosphotyrosine inmeasured by absorbance at 450 nm.

The ErbB2 kinase is as above using 250 ng/mL erbB2 intracellular domainin place of EGFR. The intracellular domain of the ErbB2 tyrosine kinase(amino acids 691-1255) is expressed as a his-tagged protein inBaculovirus and purified by nickel chelating, ion exchange and sizeexclusion chromatography.

Compounds of the present invention have IC₅₀'s from less than 1 nM to 50mM.

Example B Cellular ErbB2 Phosphorylation Assay

The cellular potency of compounds is measured by the inhibition ofphosphorylated erbB2 (p-erbB2) in the BT474 cell line whichoverexpresses erbB2 and consequently, has high basal levels of p-erbB2.BT474 cells are plated in 96 well plates and incubated overnight at 37°C./5% CO₂. The next day, the medium is replaced with serum-free medium,followed by the addition of compounds for 2 hours. Cells are lysed bythe addition of lysis buffer and freezing at −80° C. Thawed andclarified lysates are then added to 96-well plates that are coated withan anti-erbB2 antibody. Phosphorylated erbB2 is detected with aphospho-tyrosine antibody using an ELISA format. Compounds of thepresent invention have IC₅₀'s of less than 1 μM in this assay.

Example C Cellular EGFR Phosphorylation Assay

This assay measures the inhibition of EGF-induced phosphorylated EGFR(pEGFR) in the A431 cell line which overexpresses EGFR. Cells are platedin 96 well plates and incubated for 6-8 hrs at 37° C./5% CO₂ beforebeing serum-starved overnight. The next day, compounds are added for 1hour before a 10 minute induction with EGF. Cells are lysed by theaddition of lysis buffer and freezing at −80° C. Thawed and clarifiedlysates are then added to 96-well plates that are coated with ananti-EGFR antibody; p-EGFR is then detected by a phospho-tyrosineantibody using an ELISA format.

PREPARATIVE EXAMPLES

In order to illustrate the invention, the following examples areincluded. However, it is to be understood that these examples do notlimit the invention and are only meant to suggest a method of practicingthe invention. Persons skilled in the art will recognize that thechemical reactions described may be readily adapted to prepare a numberof other compounds of the invention, and alternative methods forpreparing the compounds of this invention are deemed to be within thescope of this invention. For example, the synthesis of non-exemplifiedcompounds according to the invention may be successfully performed bymodifications apparent to those skilled in the art, e.g., byappropriately protecting interfering groups, by utilizing other suitablereagents known in the art other than those described, and/or by makingroutine modifications of reaction conditions. Alternatively, otherreactions disclosed herein or known in the art will be recognized ashaving applicability for preparing other compounds of the invention.

In the examples described below, unless otherwise indicated alltemperatures are set forth in degrees Celsius. Reagents were purchasedfrom commercial suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge, and were used without further purification unlessotherwise indicated. Tetrahydrofuran (THF), N,N-dimethylformamide (DMF),dichloromethane (DCM), dichloroethane (DCE), toluene, dioxane and1,2-difluoroethane were purchased from Aldrich in Sure seal bottles andused as received.

The reactions set forth below were done generally under a positivepressure of nitrogen or argon or with a drying tube (unless otherwisestated) in anhydrous solvents, and the reaction flasks were typicallyfitted with rubber septa for the introduction of substrates and reagentsvia syringe. Glassware was oven dried and/or heat dried.

Column chromatography was done on a Biotage system (Manufacturer: DyaxCorporation) having a silica gel column or on a silica SepPak cartridge(Waters). ¹H NMR spectra were recorded on a Varian instrument operatingat 400 MHz. ¹H-NMR spectra were obtained as CDCl₃, CD₃OD or d₆-DMSOsolutions (reported in ppm), using TMS as the reference standard (0.0ppm). When peak multiplicities are reported, the following abbreviationsare used; s (singlet), d (doublet), t (triplet), m (multiplet), br(broadened), dd (doublet of doublets), dt (doublet of triplets).Coupling constants, when given, are reported in Hertz (Hz).

Example 1

Synthesis ofN6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenyl)quinazoline-4,6-diamine

Step A: Preparation ofN′-(2-cyano-4-nitrophenyl)-N,N-dimethylformamidine: A mixture of2-amino-5-nitrobenzonitrile (30.0 g, 184 mmol) anddimethoxy-N,N-dimethylmethanamine (29.6 mL, 223 mmol) was heated to 100°C. for 2 hours. The reaction mixture was concentrated under reducedpressure and dissolved in dichloromethane. The solution was run througha silica plug washing the plug with ethyl acetate. The filtrate wasconcentrated under reduced pressure, stirred with ether and filtered toprovide the product (35.0 g, 87%) as yellow solid.

Step B: Preparation ofN′-(4-amino-2-cyanophenyl)-N,N-dimethylformamidine: A solution ofN′-2-cyano-4-nitrophenyl)-N,N-dimethylformamidine (30.0 g, 137 mmol),cyclohexene (200 mL) and 10% Pd on carbon (3.0 g) in methanol (1 L) wasrefluxed for 10 hours under a hydrogen atmosphere. The hot solution wasfiltered through Celite and the filtrate was concentrated under reducedpressure. The residue was recrystallized from dichloromethane/carbontetrachloride to provide the product (23.4 g, 90%) as pale graycrystals.

Step C: Preparation of1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea:To a cooled (−10° C.) solution of thiocarbonyldiimidazole (211 g, 1.178mol) in THF (1.5 L) was added slowly via cannula a solution ofN′-(4-amino-2-cyanophenyl)-N,N-dimethylformamidine (201.6 g, 1.071 mol)in THF (1.5 L). After stirring at −10° C. for 25 minutes, a solution of2-amino-2-methylpropan-1-ol (120 g, 1.4 mol) in THF (500 mL) was slowlyadded to the mixture. After warming to room temperature and stirring for16 hours, the mixture was washed with saturated sodium chloride (2×2 L).The combined aqueous layers were extracted with MTBE (2 L) and ethylacetate (4×1 L). The combined organic layers were dried over MgSO₄ andconcentrated under reduced pressure. The residue was crystallized withMTBE and ethyl acetate to provide the product (116.9 g, 34%) as yellowsolid.

Step D: Preparation of 1-(2,5-dihydroxyphenyl)ethanone oxime: To asolution of 1-(2,5-dihydroxyphenyl)ethanone (10.0 g, 65.73 mmol) inethanol (200 mL) was added hydroxylamine hydrochloride (13.7 g, 197.2mmol). After heating to reflux for 16 hours, the solvent was reducedunder reduced pressure. Ethyl acetate (200 mL) and water were added andthe mixture was extracted with ethyl acetate (3×). The combined organiclayers were dried and concentrated to provide the product (10 g, 91%) asyellow solid.

Step E: Preparation of 2-methylbenzo[d]oxazol-5-ol: To a cooled (0° C.)solution of 1-(2,5-dihydroxyphenyl)ethanone oxime (1.0 g, 5.98 mmol) inDMF (30 mL) was added dropwise POCl₃ (0.661 mL, 6.58 mmol). Afterstirring at 0° C. for 1 hour and then at room temperature for 2 hours,the mixture was washed with water. The aqueous layer was extracted withethyl acetate and the combined organics were dried and concentratedunder reduced pressure to provide the crude product that was usedwithout further purification.

Step F: Preparation of2-methyl-5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole:2-Methylbenzo[d]oxazol-5-ol (0.86 g, 5.77 mmol),1-fluoro-2-methyl-4-nitrobenzene (0.98 g, 6.34 mmol) and K₂CO₃ (1.59 g,11.53 mmol) were combined in DMF and heated to 50° C. for 16 hours. Thereaction mixture was cooled to room temperature and poured into icewater. The mixture was extracted with ethyl acetate (3×). The combinedorganics were washed with brine, dried, and concentrated under reducedpressure. The residue was chromatographed (20% to 40% ethyl acetate inhexanes) to provide the product (0.671 g, 41%) as yellow solid.

Step G: Preparation of3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine: To a solution of2-methyl-5-(2-methyl-4-nitrophenoxy)methylbenzo[d]oxazole (671 mg, 2.36mmol) in ethanol (10 mL) was added 10% palladium on carbon (50 mg, 0.047mmol). The reaction mixture was subjected to 40 psi of hydrogen for 2.5hours. The mixture was filtered and the filtrate was concentrated underreduced pressure. The residue was chromatographed to provide the product(0.411 g, 69%) as yellow oil.

Step H: Preparation of1-(1-hydroxy-2-methylpropan-2-yl)-3-(4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenylamino)quinazolin-6-yl)thiourea:To a solution of1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea(275 mg, 0.861 mmol) and3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine (241 mg, 0.947mmol) in isopropyl acetate (2 mL) was added acetic acid (0.2 mL, 3.44mmol). After stirring at room temperature for 16 hours, hexanes wasadded and stirred with the mixture for 30 minutes. The mixture wasfiltered to provide the crude product (281 mg, 62%) as yellow solid.

Step 1: Preparation ofN6-(4,4-dimethyl-4,5-dihydrooxazol-3-yl)-N4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenyl)quinazoline-4,6-diamine:To a solution of1-(1-hydroxy-2-methylpropan-2-yl)-3-(4-(3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)phenylamino)quinazolin-6-yl)thiourea(156 mg, 0.295 mmol) and NaOH (71 mg, 1.77 mmol) in THF (5 mL) was addedtosylchloride (113 mg, 0.590 mmol). After stirring at room temperaturefor 3 hours, water was added and the mixture was extracted with ethylacetate (2×). The combined organics were washed with 1M NaOH and thenbrine. The solution was dried and concentrated under reduced pressure.The yellow residue was chromatographed to isolate a white solid. Thesolid was triturated with ether and chromatographed again to provide thepure product (92 mg, 63%) as white solid. MS APCI (+) m/z 495 (M+1)detected; ¹H-NMR (400 MHz, DMSO-d6) δ 9.49 (br. s, 1H), 8.45 (s, 1H),7.95 (br. s, 1H), 7.81 (br. s, 1H), 7.73 (br. m, 2H), 7.65 (s, 1H), 7.62(s, 1H), 7.46 (br. s, 1H), 7.12 (d, 1H), 6.97 (dd, 1H), 6.93 (d, 1H),4.08 (m, 2H), 2.60 (s, 3H), 2.21 (s, 3H), 1.28 (s, 6H).

Example 2

N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N4-(3-methyl-4-(2-methylbenzo[d]oxazol-6-yloxy)phenyl)quinzaoline-4,6-diamine

Prepared according to the procedure for Example 1 using1-(2,4-dihydroxyphenyl)ethanone in place of1-(2,5-dihydroxyphenyl)ethanone. MS APCI (+) m/z 495 (M+1) detected;¹H-NMR (400 MHz, DMSO-d6) δ9.49 (s, 1H), 8.45 (s, 1H), 7.95 (br. s, 1H),7.83 (br. s, 1H), 7.76 (br. s, 1H), 7.65 (br. s, 1H), 7.61 (d, 1H, J=8Hz), 7.20 (d, 1H, J=2 Hz), 6.96 (d, 1H, J=8 Hz), 6.93 (dd, 1H, J=8 Hz, 2Hz), 4.09 (br. s, 2H), 2.58 (s, 3H), 2.21 (s, 3H), 1.28 (s, 6H).

Example 3

N6-(4,4-dimethyloxazolidin-2-ylidene)-N4-(3-methyl-4-(2-methylbenzo[d]thiazol-5-yloxy)phenyl)quinazoline-4,6-diamine

Prepared according to the procedure for Example 1 using2-methylbenzo[d]thiazol-5-ol in place of 2-methylbenzo[d]oxazol-5-ol. MSAPCI (+) m/z 511 (M+1) detected; ¹H-NMR (400 MHz, DMSO-d6) δ 9.53 (s,1H), 8.47 (s, 1H), 8.02 (s, 1H), 8.00 (d, 1H, J=8 Hz), 7.83 (s, 1H),7.75 (d, 1H, J=7 Hz), 7.66 (d, 1H, J=8 Hz), 7.29 (d, 1H, J=2 Hz), 7.08(dd, 1H, J=8 Hz, 2 Hz), 7.03 (d, 1H, J=8 Hz), 4.08 (s, 2H), 2.77 (s,3H), 2.20 (s, 3H), 1.28 (s, 6H).

Example 4

N6-(4,4-dimethyloxazolidin-2-ylidene)-N4-(3-methyl-4-(2-methylbenzo[d]thiazol-6-yloxy)phenyl)quinazoline-4,6-diamine

Step A: Preparation of 2-methylbenzo[d]thiazole-6-ol: To a cooled (−78°C.) solution of 6-methoxy-2-methylbenzo[d]thiazole (0.861 g, 4.80 mmol)in dichloromethane (10 mL) was added BBr₃ (5 mL of 1.0 M solution indichloromethane). After slowly warming to room temperature and stirringfor 16 hours, the mixture was cooled to 0° C. and slowly quenched withmethanol (20 mL). The reaction mixture was warmed to room temperatureand concentrated under reduced pressure. The residue was partitionedbetween saturated NaHCO₃ and dichloromethane/isopropyl alcohol (85/15).The organic layer was dried over Na₂SO₄, filtered, and concentratedunder reduced pressure to provide the crude product (0.351 g, 44%) thatwas used without further purification.

Step B: The title compound was prepared according to the procedure forExample 1 using 2-methylbenzo[d]thiazol-6-ol in place of2-methylbenzo[d]oxazol-5-ol. MS APCI (+) m/z 511 (M+1) detected; ¹H-NMR(400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.46 (s, 1H), 8.03 (br. s, 1H), 7.87(d, 1H, J=9 Hz), 7.83 (s, 1H), 7.75 (d, 1H, J=8 Hz), 7.65 (d, 1H, J=8Hz), 7.50 (d, 1H, J=2 Hz), 7.10 (dd, 1H, J=8 Hz, 2 Hz), 7.00 (d, 1H, J=8Hz), 4.07 (s, 2H), 2.76 (s, 3H), 2.20 (s, 3H), 1.28 (s, 6H).

Example 5

N6-(4,4-dimethyloxazolidin-2-ylidene-2-ylidene)-N4-(3-methyl-4-(quinolin-6-yloxy)phenyl)quinazoline-4,6-diamine

Prepared according to the procedure for Example 1 using quinolin-6-ol inplace of 2-methylbenzo[d]oxazol-5-ol. MS APCI (+) m/z 491 (M+1)detected; ¹H-NMR (400 MHz, DMSO-d6) δ 9.54 (s, 1H), 8.78 (dd, 1H, J=5Hz, 2 Hz), 8.48 (s, 1H), 8.25 (d, 1H, J=9 Hz), 8.05 (d, 1H, J=9 Hz),7.89 (s, 1H), 7.82 (d, 1H, J=8 Hz), 7.66 (d, 1H, J=9 Hz), 7.56 (dd, 2H,J=9 Hz, 3 Hz), 7.46 (dd, 2H, J=9 Hz, 5 Hz), 7.16 (d, 2H, J=2 Hz), 7.10(d, 1H, J=9 Hz), 4.08 (s, 2H), 2.21 (s, 3H), 1.29 (s, 6H).

Example 6

N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N4-(4-(isoquinolin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine

Prepared according to the procedure for Example 1 using isoquinolin-7-olin place of 2-methylbenzo[d]oxazol-5-ol. MS APCI (+) m/z 491 (M+1)detected; ¹H-NMR (400 MHz, DMSO-d6) δ 9.58 (s, 1H), 9.18 (s, 1H), 8.49(s, 1H), 8.41 (d, 1H), 8.04 (br. s, 1H), 8.03 (d, 1H), 7.90 (s, 1H),7.85 (d, 1H), 7.81 (d, 2H), 7.67 (d, 1H), 7.60 (dd, 2H), 7.28 (d, 1H),7.12 (d, 1H), 4.08 (s, 2H), 2.20 (s, 3H), 1.29 (s, 6H).

Example 7

N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N4-(3-methyl-4-(quinolin-7-yloxy)phenyl)quinazoline-4,6-diamine

Prepared according to the procedure for Example 1 using quinolin-7-ol inplace of 2-methylbenzo[d]oxazol-5-ol. MS APCI (+) m/z 491 (M+1)detected; ¹H-NMR (400 MHz, DMSO-d6) δ 9.59 (s, 1H), 8.81 (dd, 1H, J=2Hz, 5 Hz), 8.49 (s, 1H), 8.34 (d, 1H, J=8 Hz), 8.04 (br. s, 1H), 8.02(d, 1H, J=9 Hz), 7.89 (br. s, 1H), 7.84 (d, 1H, J=9 Hz), 7.66 (d, 1H,J=9 Hz), 7.43 (m, 3H), 7.16 (d, 1H, J=9 Hz), 7.09 (d, 1H, J=2 Hz), 4.08(s, 2H), 2.19 (s, 3H), 1.76 (s, 6H).

Example 8

N4-(4-(benzo[d]thiazol-6-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

Step A: Preparation of benzo[d]thiazol-6-ol: 6-methoxybenzo[d]thiazolehydrobromide (1.00 g, 4.06 mmol) was dissolved in aqueous hydrobromide(10 mL of 48% solution). After heating to reflux for 10 hours, themixture was cooled in an ice bath and diluted with water (50 mL). Afteradjusting the pH to 8 with the slow addition of solid NaHCO₃, themixture was filtered, washing the solid with water and air-drying toprovide the product (0.35 g, 57%) as white solid.

Step B: The title compound was prepared according to the procedure forExample 1 using benzo[d]thiazol-6-ol in place of2-methylbenzo[d]oxazol-5-ol. MS APCI (+) m/z 497 (M+1) detected; ¹H-NMR(400 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.26 (s, 1H), 8.47 (s, 1H), 8.06 (d,1H, J=9 Hz), 8.01 (br. s, 1H), 7.85 (s, 1H), 7.77 (d, 1H, J=8 Hz), 7.66(d, 1H, J=8 Hz), 7.61 (d, 1H, J=2 Hz), 7.20 (dd, 1H, J=9 Hz, 2 Hz), 7.03(d, 1H, J=9 Hz), 4.07 (s, 2H), 2.21 (s, 3H), 1.28 (s, 6H).

Example 9

N4-(4-([1,2,4]triazolo[4,3-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

Step A: Preparation of 4-(benzyloxy)-2-chloropyridine: To a cooled (0°C.) slurry of washed (hexanes) sodium hydride (14.07 g, 352 mmol) in THF(650 mL) was added dropwise a solution of benzyl alcohol (35.2 mL, 337mmol) in THF (200 mL). After stirring for 15 minutes, a solution of2-chloro-4-nitropyridine (50 g, 306 mmol) in THF (200 mL) was addeddropwise. After heating to reflux for 16 hours, the black slurry wasdiluted with water (200 mL) and concentrated to remove the THF. Theresulting mixture was diluted with more water and filtered. The filtratewas extracted with ether and ethyl acetate. The combine organics weredried and concentrated. The residue was chromatographed (10% ethylacetate in hexanes) to provide the product as orange solid.

Step B: Preparation of 1-(4-(benzyloxy)pyridin-2-yl)hydrazine: To asolution of 4-(benzyloxy)-2-chloropyridine (4.89 g, 22.30 mmol) inpyridine (120 mL) was added hydrazine (45 mL, 22.30 mmol). After heatingto reflux for 18 hours, the mixture was concentrated to provide thecrude product, which was used without further purification.

Step C: Preparation of 7-(benzyloxy)-[1,2,4]triazolo[4,3-a]pyridine: Toa solution of 1-(4-(benzyloxy)pryidin-2-yl)hydrazine (3.52 g, 16.35mmol) in trimethoxymethane (20 mL, 16.35 mmol) was added4-methylbenzenesulfonic acid (2.816 g, 16.35 mmol). After heating to 60°C. for 2 hours, the reaction mixture was concentrated under reducedpressure. The residue was chromatographed (ethyl acetate and 20:1dichloromethane/methanol) to provide the product (2.33 g, 63%).

Step D: Preparation of [1,2,4]triazolo[4,3-a]pyridin-7-ol: To a solutionof 7-(benzoyloxy)-[1,2,4]triazolo[4,3-a]pyridine (0.512 g, 2.27 mmol) inethanol (30 mL) as added Pd/C (0.5 g). After stirring under a hydrogenballoon for 3 hours, the mixture was filtered through celite and washedwith ethanol (30 mL). The filtrate was concentrated under reducedpressure and chromatographed (20:1 dichloromethane/methanol) to providethe product.

Step E: The title compound was prepared according to the procedure forExample 1 using [1,2,4]triazolo[4,3-a]pyridin-7-ol in place of2-methylbenzo[d]oxazol-5-ol. MS ESI (+) m/z 481 (M+1) detected; ¹H-NMR(400 MHz, CDCl₃) δ 8.79 (s, 1H), 8.85 (s, 1H), 8.19 (m, 2H), 7.95 (s,1H), 7.74 (m, 3H), 7.53 (d, 1H), 7.12 (d, 1H), 6.89 (dd, 1H), 6.79 (s,1H), 4.14 (s, 2H), 2.26 (s, 3H), 1.46 (s, 6H).

Example 10

Synthesis ofN4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine.

Step A: Preparation of 4-(benzyloxy)pyridin-2-amine: To a mixture of4-(benzyloxy)-2-chloropyridine (1.10 g, 5.01 mmol), Pd₂dba₃ (46 mg, 0.05mmol) and 2-(dicyclohexylphosphino)-2′,4′,6′-tri-i-propyl-1,1′-biphenyl(57 mg, 0.120 mmol) in THF (10 mL) was added LHMDS (6 mL of 1.0 Msolution). After heating to 65° C. for 30 minutes, the mixture wascooled to room temperature and concentrated onto silica gel. The productwas eluted with 20:1 ethyl acetate/methanol to isolate a pale gold solid(0.97 g, 96%).

Step B: Preparation of tert-butyl 4-(benzyloxy)pyridin-2-ylcarbamate: Toa solution of 4-(benzyloxy)pyridin-2-amine (4.6 g, 22.97 mmol) in tBuOH(50 mL) was added boc-anhydride (5.57 g, 25.5 mmol). After heating to50° C. for 1 hour, ethanol (200 mL) was added to the reaction mixture.The room temperature mixture was filtered to provide the solid product(5.89 g, 85%).

Step C: Preparation of tert-butyl 4-hydroxypyridin-2-ylcarbamate: To asolution of tert-butyl 4-(benzyloxy)pyridin-2-ylcarbamate (5.89 g, 19.6mmol) in methanol was added palladium on carbon (1.04 g, 0.981 mmol).After stirring under a hydrogen balloon at room temperature for 70minutes, the solids were removed by filtration. The filtrate wasconcentrated under reduced pressure and solidified under high vacuum toprovide the product (4.12 g, 99%) as white solid.

Step D: Preparation of tert-butyl4-(2-methyl-4-nitrophenoxy)pyridin-2-ylcarbamate: To a solution oftert-butyl 4-hydroxypyridin-2-ylcarbamate (4.12 g, 19.6 mmol) and1-fluoro-2-methyl-4-nitrobenzene (3.34 g, 21.6 mmol) in DMF (40 mL) wasadded K₂CO₃ (4.06 g, 29.04 mmol). After heating to 65° C. for 64 hours,the mixture was cooled to room temperature and poured into ice water(200 mL). The reaction mixture was extracted several times with ethylacetate. The combined organics were concentrated under reduced pressure.The residue was chromatographed (20% ethyl acetate in hexanes) toprovide the product (2.03 g, 30%).

Step E: Preparation of 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine: To asolution of tert-butyl 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylcarbamate(1.0 g, 2.90 mmol) in dichloromethane (28 mL) was added TFA (4 mL).After stirring at room temperature for 6 hours, the reaction mixture wasconcentrated under reduced pressure to provide the crude product thatwas used without further purification.

Step F: Preparation of7-(2-methyl-4-nitrophenoxy)H-imidazo[1,2-a]pyridine: To a solution of4-(2-methyl-nitrophenoxy)pyridin-2-amine (0.71 g, 2.90 mmol) indichloromethane (25 mL) was added saturated NaHCO₃ (25 mL) followed bychloroacetaldehyde (1.14 g, 7.24 mmol). After stirring at roomtemperature for 16 hours, the mixture was diluted with water anddichloromethane. The aqueous layer was extracted with dichloromethaneand the combined organics were dried and concentrated under reducedpressure. The residue was chromatographed to provide the product (0.61g, 78%) as sticky yellow solid.

Step G: Preparation of4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylbenzenamine: To a solutionof 7-(2-methyl-4-nitrophenoxy)H-imidazo[1,2-a]pyridine (0.59 g, 2.19mmol) in ethanol was added palladium on carbon (0.116 g, 0.11 mmol).After stirring at room temperature under a hydrogen balloon for 16hours, the solids were removed by filtration. The filtrate wasconcentrated under reduced pressure and solidified under high vacuum toprovide the product (0.51 g, 97%) as white foam.

Step H: Preparation ofN4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihdyrooxazol-2-yl)quinazoline-4,6-diamine:To a mixture of 4-(H-imidazol[1,2-a]pyridin-7-yloxy)-3-methylbenzenamine(0.124 g, 0.518 mmol) and1-(3-cyano-4-((dimethylamino))methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea(0.151 g, 0.471 mmol) in isopropyl acetate (2 mL) was added acetic acid(1 mL). After stirring at room temperature for 16 hours, hexanes wereadded to the mixture and the yellow solid was collected by filtration.To a solution of this product dissolved in THF (1 mL) was added tosylchloride (0.180 g, 0.942 mmol) and NaOH (2.8 mL of 1 M solution). Afterstirring at room temperature for 30 minutes, water was added to themixture and it was extracted with ethyl acetate twice. The combinedorganics were washed with NaOH (1 M) and brine. The solution was dried,filtered, and concentrated under reduced pressure. The yellow residuewas triturated with ethyl acetate/MTBE to provide the product (0.10 g,44%) as white solid. MS APCI (+) m/z 480 (M+1) detected; ¹H NMR (400MHz, DMSO-d6) δ 9.55 (s, 1H), 8.54 (d, 1H, J=7 Hz), 8.48 (s, 1H), 8.00(br. s, 1H), 7.94 (m, 3H), 7.66 (d, 1H, J=8 Hz), 7.50 (br. s, 1H), 7.43(s, 1H), 7.12 (d, 1H, J=8 Hz), 6.80 (dd, 1H, J=7 Hz, 2 Hz), 6.53 (d, 1H,J=2 Hz), 4.08 (br. s, 2H), 2.19 (s, 3H), 1.28 (s, 6H).

Example 11

N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

Step A: Preparation of(Z)-N,N-dimethyl-N′-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)formamidine:To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-amine (2.05 g,8.34 mmol) in ethanol (9 mL) was added dimethoxy-N,N-dimethylmethanamine(1.18 mL, 8.34 mmol). After heating to 80° C. for 1 hour, the mixturewas concentrated under reduced pressure to provide the crude product asdark oil.

Step B: Preparation of7-(2-methyl-4-nitrophenoxy)-[1,2,4]-triazolo[1,5-a]pyridine: to a cooled(0° C.) solution of(Z)-N,N-dimethyl-N′-(4-(2-methyl-4-nitrophenoxy)pyridin-2-yl)formamidine(1.00 g, 3.33 mmol) in methanol (5 mL) was added pyridine (0.54 mL, 6.66mmol) and hydroxylamine sulfonic acid (0.427 g, 3.66 mmol). Afterstirring at room temperature for 2 hours, the precipitate was filteredto provide the product (0.442 g, 49%) as white solid.

Step C: The title compound was prepared according to the procedure forExample 1 using[7-(2-methyl-4-nitrophenoxy)-[1,2,4]-triazolo[1,5-a]pyridine in place of2-methyl-5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole. MS APCI (+) m/z 481(M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 8 9.58 (s, 1H), 8.93 (d, 1H),8.49 (s, 1H), 8.38 (s, 1H), 7.92 (br. m, 2H), 7.67 (br. s, 1H), 7.47(br. s, 1H), 7.19 (d, 1H), 7.03 (dd, 1H), 6.79 (d, 1H), 4.08 (s, 2H),2.19 (s, 3H), 1.28 (s, 6H). Example 12

N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N4-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)quinazoline-4,6-diamine

Step A: Preparation of 4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine:To a solution of 1-fluoro-2-methyl-4-nitrobenzene (2.02 g, 13.0 mmol)and 4-amino-3-nitrophenol (2.22 g, 14.4 mmol) in DMF (20 mL) was addedcesium carbonate (5.28 g, 16.2 mmol). After heating to 60° C. for 10hours, the mixture was diluted with water (100 mL) and filtered. Theprecipitate was washed with water and air-dried to provide the product(3.28 g, 87%) as dark solid.

Step B: Preparation ofN-methyl-4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine: To a solutionof sodium hydroxide (10.2 g in 10.5 mL water) was added toluene (15 mL),4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine (2.00 g, 6.92 mmol),dimethyl sulfate (750 μL, 7.88 mmol) and tetrabutylammonium sulfate(0.277 g, 0.816 mmol). After stirring at room temperature, the cooled(0° C.) reaction mixture was diluted with water (100 mL) and extractedwith dichloromethane (100 mL). The organic layer was washed with waterand brine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was chromatographed (dichloromethane) to providethe product (1.90 g, 91%).

Step C: Preparation of4-(4-amino-2-methylphenoxy)-N1-methylbenzene-1,2-diamine: To a solutionof N-methyl-4-(2-methyl-4-nitrophenoxy)-2-nitrobenzenamine (1.90 g, 6.27mmol) in ethyl acetate (10 mL) and ethanol (20 mL) was added 10% Pd/C(0.342 g, 0.321 mmol). After shaking under 50 psi of hydrogen for 1hour, the mixture was filtered and the filtrate was concentrated underreduced pressure to provide the product as clear oil.

Step D: Preparation ofN-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)formamide:4-(4-amino-2-methylphenoxy)-N1-methylbenzene-1,2-diamine (1.52 g, 6.25mmol) was dissolved in formic acid (15 mL) and heated to reflux for 6hours. After cooling to room temperature, the mixture was diluted water(100 mL) and neutralized with sodium bicarbonate. The mixture waspartitioned between water and dichloromethane. The organic layer waswashed with aqueous NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to provide the product (1.70 g,97%).

Step E: Preparation of3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzenamine: To asolution of concentrated aqueous HCl (10 mL) in methanol (10 mL) wasaddedN-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)formamide(1.70 g, 6.04 mmol). After heating to reflux for 2 hours, the reactionmixture was cooled to room temperature and diluted with water (100 mL).The mixture was neutralized with sodium bicarbonate and extracted withdichloromethane. The organic solution was dried over Na₂SO₄, filteredand concentrated under reduced pressure to provide the product.

Step F: The title compound was prepared according to the procedure forExample 1 using3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzenamine in place of3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine. MS APCI (+) m/z494 (M+1) detected; ¹H-NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1H), 8.44 (s,1H), 8.17 (s, 1H), 8.00 (br. s, 1H), 7.78 (s, 1H), 7.66 (m, 2H), 7.56(c, 1H), 7.08 (d, 1H), 6.98 (dd, 1H), 6.86 (d, 1H), 4.07 (s, 2H), 3.84(s, 3H), 2.23 (s, 3H), 1.28 (s, 6H).

Example 13

N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-N4-(3-methyl-4-(2-methylH-imidazo[1,2-a]pyridin-7-yloxy)phenyl)quinazoline-4,6-diamine

Prepared according to the procedure for Example 10 using chloroacetonein place of chloroacetaldehyde. MS APCI (+) m/z 494 (M+1) detected;¹H-NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.43 (d, 1H), 7.87 (m, 3H),7.66 (br, s, 1H), 7.56 (s, 2H), 7.10 (d, 1H), 6.71 (dd, 1H), 6.45 (s,1H), 4.09 (s, 2H), 2.25 (s, 3H), 2.18 (s, 3H), 1.11 (s, 6H). Example 14

N4-(4-(H-imidazo[1,2-a]pyridin-6-yloxy)-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

Step A: Preparation of 2-chloro-5-(2-methyl-4-nitrophenoxy)pyridine: Toa suspension of 6-chloropyridin-3-ol (3.37 g, 26.0 mmol) and K₂CO₃ (7.19g, 52.0 mmol) in DMF (200 mL) was added 1-fluoro-2-methyl-4-nitrobenzene(4.44 g, 28.6 mmol). After heating to 50° C. for 16 hours, the reactionmixture was cooled to room temperature and poured into water andextracted with ethyl acetate (2×). The organic layer was washed withbrine, dried over Na₂SO₄, filtered, and concentrated under reducedpressure to provide the product as yellow oil.

Step B: Preparation of 5-(2-methyl-4-nitrophenoxy)pyridin-2-amine: To asolution of 2-chloro-5-(2-methyl-4-nitrophenoxy)pyridine (1.13 g, 4.27mmol), XPHOS (0.097 g, 0.205 mmol) and Pd₂dba₃ (0.078 g, 0.0853 mmol) inTHF (32 mL) was added LHMDS (8.53 mL, 8.53 mmol). After heating to 65°C. for 1 hour, the mixture was cooled to room temperature and stirredfor 16 hours. The mixture was concentrated onto silica andchromatographed (10% methanol in ethyl acetate) to provide the product(0.336 g, 33%).

Step C: The title compound was prepared according to the procedure forExample 10 using 5-(2-methyl-4-nitrophenoxy)pyridin-2-amine in place of4-(2-methyl-4-nitrophenoxy)pyridin-2-amine. MS APCI (+) m/z 480 (M+1)detected; ¹H-NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.45 (s, 1H), 8.21(s, 1H), 7.91 (s, 1H), 7.83 (br. s, 1H), 7.73 (br. s, 1H), 7.66 (m, 2H),7.60 (d, 1H), 7.55 (s, 1H), 7.15 (dd, 1H), 7.00 (d, 1H), 4.07 (s, 2H),2.27 (s, 3H), 1.28 (s, 6H). Example 15

N-(4-(H-imidazo-[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Step A: Preparation of quinazoline-4,6-diol: A mixture of2-amino-5-hydroxybenzoic acid (19.64 g, 128 mmol), 1,3,5-triazine (15.6g, 192 mmol), and piperidine (9 mL, 92.4 mmol) were heated to 60° C. inmethanol (60 mL) for 2 hours. After cooling to 0° C., the mixture wasfiltered. The solid was washed with cold methanol and dried under highvacuum to provide the product (15 g, 72%) as white solid.

Step B: Preparation of 4-hydroxyquinazolin-6-yl acetate: A mixture ofquinazoline-4,6-diol (20 g, 123 mmol) and acetic anhydride (186 mL, 1.97mol) was heated to 100° C. in pyridine (30 mL) for 2 hours. Aftercooling to room temperature, ice (200 g) was slowly added to thereaction mixture. The precipitate was filtered, washed with cold water,and dried under high vacuum to provide the product (16.25 g, 65%) aspale yellow solid.

Step C: Preparation of 4-chloroquinazolin-6-yl acetate: To a solution of4-hydroxyquinazolin-6-yl acetate (12.0 g, 58.8 mmol) in thionyl chloride(50 mL) was added DMF (0.5 mL). After heating to 90° C. for 3 hours, thereaction mixture was concentrated under reduced pressure and azeotropedwith toluene to provide the product (11.8 g, 90%) as off-white solid.

Step D: Preparation of4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-ylacetate hydrochloride: A mixture of 4-chloroquinazolin-6-yl acetate (930mg, 4.18 mmol) and4-(H-imidazo[1,2-a])pyridin-7-yloxy)-3-methylbenzenamine (1.10 g, 4.60mmol) dissolved in isopropanol (20 mL) was heated to reflux for 2 hours.After cooling to room temperature, the precipitate was collected viafiltration and washed with isopropanol and ether. The precipitate wasair-dried to provide the product (820 mg, 43%).

Step E: Preparation of4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-ol:To a solution of4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-ylacetate hydrochloride (820 mg, 1.78 mmol) in THF (30 mL) was addedammonium hydroxide (10 mL). After stirring at room temperature forseveral hours, the precipitate was collected via filtration and washedwith THF. The precipitate was air-dried to provide the product (581 mg,85%) as white solid.

Step F: Preparation ofN-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine:A mixture of4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-ol(578 mg, 1.27 mmol), cesium carbonate (1.60 g, 4.91 mmol), sodium iodide(190 mg, 1.27 mmol) and 1-bromo-2-methoxyethane (150 μL, 1.58 mmol) inDMF (10 mL) was heated to 80° C. for 3 hours. After cooling to roomtemperature, the mixture was partitioned between dichloromethane andwater. The organic layer was washed with water (4×) and brine, driedover Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was chromatographed (100:7:0.1dichloromethane/methanol/triethylamine) to provide the product (365 mg,65%) as foam. To 325 mg of this product dissolved in methanol (10 mL)was added tosylic acid monohydrate (280 mg). After stirring at roomtemperature for 45 minutes, the mixture was concentrated under reducedpressure. The residue was triturated with ether, filtered and air-driedto provide the product (576 mg) as the bis-tosylate salt. MS APCI (+)m/z 442 (M+1) detected; ¹H-NMR (400 MHz, CD₃OD) δ 7.46 (d, 1H, J=8 Hz),7.43 (s, 1H), 6.79 (dd, 2H, J=11 Hz, 2 Hz), 6.54 (m, 2H), 6.52 (s, 1H),6.49 (dd, 1H, J=9Hz, 2 Hz), 6.45 (dd, 1H, J=9 Hz, 3 Hz), 6.38 (d, 4H,J=9 Hz), 6.02 (dd, 1H, J=7 Hz, 2 Hz), 5.99 (d, 1H, J=9 Hz), 5.89 (d, 4H,J=9 Hz), 5.71 (d, 1H, J=3 Hz), 3.07 (m, 2H), 2.51 (m, 2H), 2.15 (s, 3H),1.04 (s, 6H), 0.95 (s, 3H).

Example 16

N-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-(cyclopropylmethoxy)quinazolin-4-amine

Prepared according to the procedure for Example 15 using(bromomethyl)cyclopropane in place of 1-bromo-2-methoxyethane. MS APCI(+) m/z 438 (M+1) detected; ¹H-NMR (400 MHz, CDCl₃) δ 8.97 (s, 1H), 8.67(s, 1H), 8.07 (d, 1H, J=8 Hz), 7.82 (d, 1H, J=9 Hz), 7.65 (d, 1H, J=2Hz), 7.50 (m, 3H), 7.44 (dd, 2H, J=9 Hz, 2 Hz), 6.93 (d, 1H, J=9 Hz),6.74 (dd, 1H, J=7 Hz, 2 Hz), 6.54 (d, 1H, J=2 Hz), 3.72 (d, 2H, J=7 Hz),2.11 (s, 3H), 1.24 (m, 1H), 0.59 (m, 2H), 0.21 (m, 2H).

Example 17

(E)-N-(4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide

Step A: Preparation of 6-nitroquinazolin-4-ol: A mixture of2-amino-5-nitrobenzoic acid (1000 g, 5 mol) and formamidine acetate(1000 g, 10 mol) were dissolved in methoxyethanol (4 L) and heated to115° C. for 16 hours. After cooling the mixture to room temperature, icewater (5 L) was added and the mixture was stirred for 30 minutes beforecollecting the product (125 g, 14%) by filtration.

Step B: Preparation of 4-chloro-6-nitroquinazoline: To a solution of6-nitroquinazolin-4-ol (4.40 g, 23.01 mmol) andN-ethy-N-isopropylpropan-2-amine (11.89 g, 92.04 mmol) in dichloroethane(50 mL) was added phosphoryl trichloride (7.06 g, 46.02 mmol). Afterheating to 80° C. for 16 hours, the mixture was concentrated underreduced pressure. The residue was concentrated again with toluene (2×100mL) to provide the product.

Step C: Preparation ofN-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-nitroquinazolin-4-amine:To a solution of 4-chloro-6-nitroquinazoline (4.62 g, 22.02 mmol) indichloroethane/t-butanol (20 mL, 1:1) was added4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylbenzenamine (5.270 g, 22.02mmol). After heating to 80° C. for 2 hours, the mixture was cooled to 0°C. and filtered. The solid was washed with cold dichloromethane (50 mL)to provide the product as the HCl salt. The solid was suspended indichloromethane/isopropanol (50 mL/8 mL) and washed with saturatedNaHCO₃ (50 mL). The aqueous layer was extracted with dichloromethane(2×50 mL). The combined organics were dried over Na₂SO₄ and concentratedto provide the product (7.05 g, 78%).

Step D: Preparation ofN4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine:ToN-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-nitroquinazolin-4-amine(4.665 g, 11.31 mmol) in ethanol (100 mL) was added Pd/C (1 g). Afterstirring at room temperature under a hydrogen balloon for 4 hours, themixture was filtered through celite and the solids were washed withethanol (100 mL). The filtrate was concentrated under reduced pressureto provide the product (3.89 g, 90%).

Step E: Preparation of (E)-4-(dimethylamino)but-2-enoyl chloridehydrochloride: To (E)-4-(dimethylamino)but-2-enoic acid hydrochloride(110 mg, 0.664 mmol) in acetonitrile (1.5 mL) was added oxalyldichloride (75.9 mg, 0.598 mmol) followed by one drop of DMF. Afterheating to 60° C. for 30 minutes, the mixture was cooled to roomtemperature and concentrated to 0.5 mL total volume. The resultingsolution was used without further purification.

Step F: Preparation of(E)-N-(4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-yl)-4-(dimethylamino)but-2-enamide:To a cooled (0° C.) solution of (E)-4-(dimethylamino)but-2-enoylchloride hydrochloride (0.122 g, 0.664 mmol) was added dropwise asolution ofN4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-4,6-diamine(0.127 g, 0.332 mmol) in NMP (1.5 mL). After stirring at 0° C. for 2hours, saturated NaHCO₃(15 mL) was added to the mixture. The aqueouslayer was extracted with ethyl acetate (2×10 mL). The combined organicswere dried over Na₂SO₄ and concentrated under reduced pressure. Theresidue was chromatographed (dichloromethane/methanol/30% NH₄OH20:1.5:0.01) to provide the product (16 mg, 10%). MS ESI (+) m/z 494(M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.96 (s, 1H), 8.63 (s, 1H),8.09 (d, 1H, J=7 Hz), 7.66 (d, 1H, J=9 Hz) 7.55 (d, 2H, J=14 Hz), 7.46(d, 1H, J=9 Hz), 7.40 (s, 1H), 7.38 (d, 1H, J=9 Hz), 7.02 (m, 1H), 6.83(d, 1H, J=9 Hz), 6.77 (d, 1H, J=8 Hz, 2 Hz), 6.43 (s, 1H), 6.34 (d, 1H,J=14 Hz), 3.08 (d, 2H, J=5 Hz), 2.24 (s, 6H), 1.98 (s, 3H).

Example 18

N-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-amine

Step A: Preparation of 6-bromothieno[2,3-d]pyrimidin-4-ol: To a solutionof thieno[2,3-d]pyrimidin-4-ol (3.0 g, 20 mmol) in glacial acetic acid(40 mL) was added bromine (6.3 g, 39 mmol). After heating to 80° C. for1.5 hours, the reaction mixture was cooled to room temperature andpoured into saturated NaHCO₃ and ice. The solid was filtered, washedwith water and dried to provide the product.

Step B: Preparation of 6-bromo-4-chlorothieno[2,3-d]pyrimidine: To6-bromothieno[2,3-d]pyrimidin-4-ol (3.0 g, 19.7 mmol) was addedphosphorus oxychloride (5 mL). After heating to 80° C. for 1.5 hours,the reaction mixture was poured into saturated NaHCO₃ and ice. The solidwas filtered, washed with water and dried to provide the product (4.06g, 83%) as brown solid.

Step C: Preparation ofN-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-bromothieno[2,3-d]pyrimidin-4-amine:To a solution of 6-bromo-4-chlorothieno[2,3-d]pyrimidine (0.569 g, 2.58mmol) and 4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylbenzenamine (0.60g. 2.51 mmol) in dichloroethane/isopropanol (11 mL) was added DIEA (0.44mL, 2.51 mmol). After heating to 60° C. for 64 hours, the reactionmixture was worked up with isopropanol/dichloromethane. The organicsolution was dried and concentrated under reduced pressure. The residuewas chromatographed (gradient 0% to 8% methanol/7N NH₃/ethyl acetate).The crude product was purified further by reverse phase liquidchromatography. MS ESI (+) m/z 452, 454 (M+1, Br pattern) detected; ¹HNMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 8.63 (d, 1H, J=7 Hz), 8.52 (s,1H), 8.10 (s, 1H), 7.94 (s, 1H), 7.82 (d, 1H, J=3 Hz), 7.78 (dd, 1H, J=3Hz, 9 Hz), 7.59 (s, 1H), 7.16 (d, 1H, J=9 Hz), 6.96 (dd, 1H, J=2 Hz, 7Hz), 6.63 (s, 1H), 2.19 (s, 3H).

Example 19

(Z)-N4-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(3-methylthiazolidin-2-ylidene)quinazoline-4,6-diamine

Step A: Preparation ofN-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-isothiocyanotoquinazolin-4-amine:To a solution ofN4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)quinazoline-3,6-diamine(0.292 g, 0.764 mmol) in THF/dichloroethane (6 mL/3 mL) was addeddi-(1H-imidazol-1-yl)methanethione (0.150 g, 0.840 mmol). After stirringat room temperature for 1 hour, 80% of the solvent was evaporated andDMF (4 mL) was added. The reaction solution was stirred for 1 hour moreto provide the crude product.

Step 8: Preparation of3-(4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-yl)-1-(2-hydroxeyethyl)-1-methylthiourea:ToN-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl-6-isothiocyanotoquinazolin-4-amine(0.324 g, 0.763 mmol) was added 2-(methylamino)ethanol (0.115 g, 1.53mmol). After stirring for 2 hours, the mixture was diluted with ethylacetate (20 mL) and water (10 mL). The organic phase was dried overNa₂SO₄ and concentrated to provide the crude product.

Step C: Preparation of(Z)-N4-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(3-methylthiazolidin-2-ylidene)quinazoline-4,6-diamine:To a solution of3-(4-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-yl)-1-(2-hydroxyethyl)-1-methylthiourea(0.38 g, 0.76 mmol) in THF (4 mL) was added NaOH (40%, 3.8 mmol)followed by 4-methylbenzene-1-sulfonyl chloride (0.29 g, 1.5 mmol).After stirring at room temperature for 2 hours, the reaction mixture wasconcentrated under reduced pressure. The residue was chromatographed(dichloromethane/methanol/30% NH₄OH 20:1:0.02) to provide the product.MS APCI (+) m/z 482 (M+1) detected; ¹H NMR (400 MHz, CDCl₃) δ 8.65 (m,2H), 8.18 (m, 2H), 7.85 (d, 1H, J=7 Hz), 7.7 (s, 1H), 7.62 (m, 1H), 7.58(s, 1H), 7.55 (s, 1H), 6.95 (m, 1H), 6.8 (m, 1H), 6.68 (m, 1H), 4.26 (m,2H), 3.78 (m, 2H), 3.2 (s, 3H), 2.15 (s, 3H).

Example 20

N4-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4-methylthiazol-2-yl)quinazoline-4,6-diamine

Step A: Preparation of 6-iodoquinazolin-4-ol: A mixture of2-amino-5-iodobenzoic acid (125 g, 475 mmol) and formamide (200 mL) washeated to 190° C. for 2 hours. After cooling to room temperature, thereaction mixture was poured into water (500 mL) and stirred for 2 hours.The solids were filtered and dried under high vacuum to provide theproduct (108 g, 83%).

Step B: Preparation of 4-chloro-6-iodoquinazoline: To a cooled (0° C.)suspension of 6-iodoquinazolin-4-ol (107.6 g, 396 mmol) and DIEA (138mL, 791 mmol) in dichloroethane (600 mL) was added POCl₃ (44.25 mL, 475mmol). After heating to 90° C. for 16 hours, the reaction mixture wascooled to room temperature and the crystals (73.8 g) collected byfiltration. The filtrate was concentrated under reduced pressure andazeotroped twice with toluene. The solids (8.3 g) were triturated withisopropanol (450 mL) and cooled in an ice bath before collecting byfiltration and drying under high vacuum. The two solids were combined toprovide the product (82.1 g, 71%) as white solid.

Step C: Preparation ofN-(4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-iodoquinazolin-4-aminehydrochloride: To a solution of 4-chloro-6-iodoquinazoline (6.07 g, 20.9mmol) in isopropanol (83 mL) was added4-(H-imidazo[1,2-a]pyridin-7-yloxy)-3-methylbenzenamine (5.00 g, 20.9mmol). After heating to 80° C. for 4 hours, the mixture was cooled toroom temperature and filtered. The solid was washed with coldisopropanol and recrystallized from isopropanol to provide the product(2.66 g, 24%) as yellow solid.

Step D: Preparation ofN4-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4-methylthiazol-2-yl)quinazoline-4,6-diamine:A solution ofN-(4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylphenyl)-6-iodoquinazolin-4-aminehydrochloride (0.20 g. 0.378 mmol) and 4-methylthiazol-2-amine (0.086 g,0.755 mmol) and sodium 2-methylpropan-2-olate (0.145 g, 1.51 mmol),Xanthphos (0.016 g, 0.028 mmol), Pd₂dba₃ (0.017 g, 0.018 mmol) intoluene (3.6 mL) was degassed and sealed. After heating to 100° C. for16 hours, the mixture was diluted with water and ethyl acetate. Theresulting solid was filtered to provide the product as brown solid. MSAPCI (+) m/z 480 (M+1) detected; ¹H NMR (400 MHz, DMSO-d6) δ 9.96 (s,1H), 8.86 (s, 1H), 8.63 (s, 1H), 8.55 (d, 1H), 7.79 (m, 5H), 7.44 (s,1H), 7.14 (d, 1H), 6.80 (dd, 1H), 6.55 (d, 1H), 2.50 (s, 3H), 2.21 (s,3H).

Example 21

N-(4-(benzo[d]oxazol-6-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Step A: Preparation of 2-aminobenzene-1,4-diol: To a solution of2-nitrobenzene-1,4-diol (3.00 g, 19.34 mmol) in ethanol (100 mL) wasadded 10% palladium on carbon (0.600 g, 0.564 mmol). After shaking under40 psi of hydrogen for 2 hours, the mixture was filtered and thefiltrated was concentrated under reduced pressure to provide the productas solid.

Step B: Preparation of benzo[d]oxazol-5-ol: To a solution of2-aminobenzene-1,4-diol (2.40 g, 19.2 mmol) in triethylorthoformate (10mL) was added 3 drops of concentrated HCl. After heating to 65° C. for30 minutes and stirring at room temperature for 16 hours, the mixturewas poured into water and extracted with ethyl acetate (2×). The organicphase was washed with HCl (2N) and saturated NaHCO₃, dried, andconcentrated under reduced pressure to provide the product (2.09 g, 81%)as red-black solid.

Step C: Preparation of 5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole: To asolution of benzo[d]oxazol-5-ol (1.50 g, 11.10 mmol) and1-fluoro-2-methyl-4-nitrobenzene (1.89 g, 12.21 mmol) in DMF was addedcesium carbonate (1.81 g, 5.55 mmol) and potassium carbonate (2.30 g,16.65 mmol). After heating to 50° C. for 16 hours, the mixture waspoured into ice water and extracted with ethyl acetate (3×). Thecombined organics were washed with brine, dried, and concentrated underreduced pressure. The residue was chromatographed (30% ethyl acetate inhexanes) to provide the product (1.69 g, 56%) as white solid.

Step D: Preparation of 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine:To a solution of 5-(2-methyl-4-nitrophenoxy)benzo[d]oxazole (1.65 g,6.12 mmol) in ethanol was added Pd/C (0.130 g, 0.122 mmol). Afterstirring under hydrogen atmosphere for 16 hours, the mixture wasfiltered and the filtrate was concentrated to provide the product (0.81g, 55%) as yellow oil.

Step E: Preparation of 4-chloroquinazolin-6-ol: A mixture of4-chloroquinazolin-6-yl acetate (10.0 g, 44.9 mmol) and ammonia (200 mLof 7N solution in methanol) were stirred together for 1 hour. Thereaction mixture was concentrated to about 3 mL and triturated withdiethyl ether to provide the product (6.50 g, 80%) as tan solid.

Step F: Preparation of 4-chloro-6-(2-methoxyethoxy)quinazoline: To asolution of 4-chloroquinazolin-6-ol (1.00 g. 5.54 mmol), triphenylphosphine (1.45 g, 5.54 mmol) and 2-methoxyethanol (0.421 g, 5.54 mmol)in dichloromethane (83 mL) was added diisopropyl azodicarboxylate (1.18g, 5.54 mmol). After stirring at room temperature for 16 hours, themixture was concentrated under reduced pressure. The residue waschromatographed (30% ethyl acetate in hexanes) to provide the product(1.15 g, 87%) as white solid.

Step G:N-(4-(benzo[d]oxazol-5-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine:To a solution of 4-chloro-6-(2-methoxyethoxy)quinazoline (0.199 g, 0.83mmol) and 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine (0.200 g, 0.83mmol) in isopropanol (2 mL) and DCE (2 mL). After heating to 80° C. for12 hours, the mixture was concentrated under reduced pressure. Theresidue was partitioned between saturated NaHCO₃ and EtOAc. The aqueousphase was extracted 2× with EtOAc, the combined organic phase was washedwith brine, dried (Na₂SO₄), filtered and condensed. The residue waschromatographed to provide the product (0.100 g, 27%) as off-whitesolids. MS APCI (+) m/z 443 (M+1) detected; ¹H NMR (400 MHz, DMSO-d6) δ9.59 (s, 1H), 8.76 (s, 1H), 8.50 (s, 1H),7.96 (s, 1H), 7.75 (m, 4H),7.52 (dd, 1H), 7.26 (m, 1H), 7.10 (m, 1H), 6.97 (d, 1H), 4.30 (m, 2H),3.76 (m, 2H), 3.36 (s, 3H), 2.24 (s, 3H).

Example 22

N-(4-(benzo[d]oxazol-5-yloxy)-3-chlorophenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Prepared according to the procedure for Example 21 using1-fluoro-2-chloro-4-nitrobenzene in place of1-fluoro-2-methyl-4-nitrobenzene, with the exception that the reductionof the nitro group was accomplished with Zn/NH₄Cl in MeOH/THF. MS APCI(+) m/z 463.3 (M+1) detected.

Example 23

N-(4-(benzo[d]oxazol-6-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Prepared according to the procedure for Example 21 using2-aminobenzene-1,5-diol in place of 2-aminobenzene-1,4-diol. MS APCI (+)m/z 443 (M+1) detected; ¹H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.69(s, 1H), 8.50 (s, 1H), 7.96 (s, 1H), 7.74 (m, 4H), 7.52 (dd, 1H), 7.29(d, 1H), 7.05 (m, 2H), 4.30 (m, 2H), 3.77 (m, 2H), 3.36 (s, 3H), 2.23(s, 3H).

Example 24

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Prepared according to the procedure for Example 21 using4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylbenzenamine in placeof 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine. MS APCI (+) m/z443.2.

Example 25

N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Step A. Preparation of4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylbenzenamine: Preparedaccording to the procedure for Example 11 using5-(2-methyl-4-nitrophenoxy)pyridin-2-amine in place of4-(2-methyl-4-nitrophenoxy)pyridin-2-amine.

Step B.N-(4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine:Prepared according to the procedure for Example 21 using4-([1,2,4]triazolo[1,5-a]pyridin-6-yloxy)-3-methylbenzenamine in placeof 4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine. MS APCI (+) m/z443.3.

Example 26

6-(2-methoxyethoxy)-N-(3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)quinazolin-4-amine

Prepared according to the procedure for Example 21 using3-methyl-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)benzenamine in place of4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine. MS APCI (+) m/z 45 (M+1)detected; ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 7.85 (s, 1H), 7.83 (d,1H, J=9 Hz), 7.56 (s, 1H), 7.53 (d, 1H, J=2 Hz), 7.49 (dd, 1H, J=9 Hz,3Hz), 7.38 (d, 1H, J=9 Hz, 2 Hz), 7.34 (d, 1H, J=9 Hz), 7.30 (d, 1H, J=3Hz), 7.08 (dd, 1H, J=9 Hz, 2 Hz), 6.87 (d, 1H, J=9 Hz), 4.23 (m, 2H),3.85 (s, 3H), 3.80 (m, 2H), 3.47 (s, 3H), 2.30 (s, 3H).

Example 27

N-(3-chloro-4-(1-methyl-1H-benzo[d]imidazol-5-yloxy)phenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Prepared according to the procedure for Example 26 using1-fluoro-2-chloro-4-nitrobenzene in place of1-fluoro-2-methyl-4-nitrobenzene, with the exception that the reductionof the nitro group was accomplished with Zn/NH₄Cl in MeOH/THF. MS APCI(+) m/z 476.3 (M+1) detected.

Example 28

N-(4-(benzo[d]thiazol-5-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-aminehydrochloride

Step A: Preparation of 4-(benzo[d]thiazol-5-yloxy)-3-methylbenzenamine:Prepared according to the procedure for Example 8 using5-methoxybenzo[d]thiazole in place of 6-methoxybenzo[d]thiazole.

Step B:N-(4-(benzo[d]thiazol-5-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine:Prepared according to the procedure for Example 21 using4-(benzo[d]thiazol-5-yloxy)-3-methylbenzenamine in place of4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine.

Example 29

N-(4-(H-pyrazolo[1,5-a]pyridin-6-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-aminehydrochloride

Prepared according to the procedure for Example 21 usingpyrazolo[1,5-a]pyridin-6-ol (Miki, Y.; et al., J. Heterocycles, 1996,43, 2249) in place of benzo[d]oxazol-5-ol. MS APCI (+) m/z 442.2 (M+1)detected.

Example 30

4-(4-(benzo[d]thiazol-6-yloxy)-3-methylphenyl)-6-(2-methoxyethoxy)quinazolin-4-amine

Prepared according to the procedure for Example 21 using4-(benzo[d]thiazol-6-yloxy)-3-methylbenzenamine in place of4-(benzo[d]oxazol-5-yloxy)-3-methylbenzenamine.

Example 31

N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorophenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

Step A: Preparation of(Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N,N-dimethylformamidine: A 250 mL,single-neck, round-bottom flask was charged with4-benzyloxy)pyridin-2-amine (6.012 g, 30.02 mmol),dimethoxy-N,N-dimethylmethanamine (5.535 ml, 39.03 mmol) and ethanol(100.1 ml). A few drops of TFA were added and the reaction was heated to50° C. for 4 hours. The reaction was cooled to ambient temperature andconcentrated. The crude product was used in the next step withoutpurification.

Step B: Preparation of(Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N-hydroxyformamidine: A 100 mL,single-neck, round-bottomed flask was charged with(Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N,N-dimethylformamidine (7.66 g, 30.0mmol), hydroxyl amine hydrochloride (2.40 g, 34.5 mmol), propan-2-ol(33.3 ml), and THF (5 ml). The reaction was heated to 50° C. for 7hours, then concentrated. The residue was titrated with EtOAc/THF andfiltered. The filtrate was concentrated and triturated withdichloromethane to provide the product as a white solid.

Step C: Preparation of 7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine:Trifluoroacetic anhydride (2.62 mL, 18.9 mmol) was added dropwise to asolution of (Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N-hydroxyformamidine(4.37 g, 17.9 mmol) in THF (180 mL), and the mixture was cooled to 0° C.The ice bath was then removed and the reaction was stirred for 12 hours.The reaction was concentrated to about 15-25 mL, then poured into 400 mLof iced 1 M NaOH. The mixture was stirred for 1 hour. The resultingwhite solids were collected by filtration, washed with hexanes, anddried under high vacuum for 1 hour to provide the desired product.

Step D: Preparation of [1,2,4]triazolo[1,5-a]pyridin-7-ol: A 250 mL,single-neck, round-bottomed flask was charged with7-(benzyloxy)-[1,2,4]triazolo[1,5-a]pyridine (3.20 g, 14.2 mmol), Pd/C(0.756 g, 0.710 mmol), and THF (125 mL). The reaction was stirred underan atmosphere of hydrogen for 16 hours, then filtered (GF paper) andconcentrated to a white solid. The solids were titrated with EtOAc andcollected by filtration to provide the desired product.

Step E: Preparation of tert-butyl 3-chloro-2,4-difluorobenzoate: A 125mL, single-neck, round-bottomed flask was charged withdi-tert-butoxy-N,N-dimethylmethanamine (48.2 ml, 201 mmol),3-chloro-2,4-difluorobenzoic acid (9.67 g, 50.2 mmol), and DMF (50 ml).The reaction was heated to 80° C. for 48 hours. After cooling to ambienttemperature, the reaction was diluted with saturated NaHCO₃ and EtOAc.The aqueous phase was extracted with EtOAc, and the combined organicphases were washed with saturated NaHCO₃ and brine, dried, filtered andconcentrated to provide the desired product as a gold oil.

Step F: Preparation of tert-butyl4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoate: Avial charged with tert-butyl 3-chloro-2,4-difluorobenzoate (0.210 g,0.845 mmol), [1,2,4]triazolo[1,5-a]pyridin-7-ol (0.114 g, 0.845 mmol),cesium carbonate (0.413 g, 1.27 mmol), and DMF (1.7 ml). The reactionwas heated to 80° C. for 12 hours, then poured into ice water. Theresulting solids were collected by filtration and purified by flashchromatography, eluting with gradient of 10% EtOAc/Hexanes to 50%EtOAc/Hexanes to provide the desired product.

Step G: Preparation of4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoic acid:A 25 ml flask was charged with tert-butyl4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoate(0.060 g, 0.16 mmol) and dichloromethane (1.6 ml). The reaction wascooled to 0° C., and 2,2,2-trifluoroacetic acid (0.50 ml, 0.16 mmol) wasadded. The reaction was stirred for 20 minutes, then warmed to ambienttemperature, stirred an additional 3 hours, and then concentrated toprovide the desired product as a colorless oily residue.

Step H: Preparation of4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzenamine:A vial was charged with4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorobenzoic acid(0.090 g, 0.2925 mmol), triethylamine (0.1223 ml, 0.8776 mmol) and DMF(1.5 ml). Diphenylphosphoryl azide (0.1630 ml, 0.7313 mmol) was added.The reaction was stirred at ambient temperature for 3 hours, then water(0.2199 ml, 0.2925 mmol) was added. The vial was sealed and heated to100° C. for 1 hour, then cooled to ambient temperature and poured into 1N NaOH/ice. The reaction was extracted with EtOAc, and the organic layerwas dried, filtered and concentrated. The residue was purified by flashchromatography, eluting with a gradient from 100% EtOAc to 10% (with 6%NH₄OH) MeOH/EtOAc.

Step 1: Preparation ofN4-(4-[1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-chloro-2-fluorophenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine:Prepared according to the procedure for Example 1, using4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3chloro-2-fluorobenzenamine inplace of 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine. MS APCI(+) m/z 519.3 (M+1, chlorine pattern) detected.

N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-2-fluoro-3-methylphenyl)-N6-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

Prepared according to the procedure of Example 31, using2,4-difluoro-3-methylbenzoic in place of 3-chloro-2,4-difluorobenzoicacid. MS APCI (+) m/z 499.3 (M+1) detected.

Example 33

(R)-N4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine

Prepared according to the procedure for Example 1 using(R)-2-aminopropan-1-ol in place of 2-amino-2-methylpropan-1-ol and4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylbenzenamine in placeof 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine. MS APCI (+)m/z 467.3 (M+1) detected.

Example 34

trans-2-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-yloxy)cyclopentanol

Step A: Preparation of4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-olhydrochloride: Prepared according to Example 15 using4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylbenzenamine in placeof 4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylaniline.

Step B: Preparation oftrans-2-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-yloxy)cyclopentanol:A 50 mL flask was charged with4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-olhydrochloride (3.117 g, 7.406 mmol), 6-oxa-bicyclo[3.1.0]hexane (0.6924ml, 7.777 mmol), cesium hydroxide monohydrate (2.736 g, 16.29 mmol), DMF(20 mL). The reaction was heated to 92° C. for 12 hours, then cooled toroom temperature and dilute with 200 mL of water. The mixture wasstirred for 24 hours. The resulting precipitate was collected byfiltration, washed with water and air dried to provide 2.80 g of thetitle compound as a racemic mixture. MS APCI (+) m/z 469.3 (M+1)detected.

Example 35

(2-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-ylamino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol

Step A: Preparation of(E)-N′-(4-(3-(1-(tert-butyldiphenylsilyloxy)-3-hydroxy-2-methylpropan2-yl)thioureido)-2-cyanophenyl)-N,N-dimethylformimidamide:Prepared according to the method of Example 1, using2-amino-3-(tert-butyldiphenylsilyloxy)-2-methylpropan-1-ol in place of2-amino-2-methylpropan-1-ol.

Step B: Preparation ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3methylphenyl)-N6-(4)-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine:Prepared according to the method of Example 1, using(E)-N′-(4-(3-(1-tert-butyldiphenylsilyloxy)-3-hydroxy-2-methylpropan-2-yl)thioureido)-2-cyanophenyl)-N,N-dimethylformimidamidein place of1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thioureaand 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylbenzenamine inplace of 4-(imidazo[1,2-a]pyridin-7-yloxy)-3-methylaniline.

Step C: Preparation of(2-(4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenylamino)quinazolin-6-ylamino)-4-methyl-4,5-dihydrooxazol-4-yl)methanol:TBAF (7.799 mmol, 7.79 mL, 1M in THF) was added to a solution ofN4-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-N6-(4-((tert-butyldiphenylsilyloxy)methyl)-4-methyl-4,5-dihydrooxazol-2-yl)quinazoline-4,6-diamine(2.866 g, 3.900 mmol) in THF (60 mL). The reaction was stirred for 3hours and then concentrated. The residue was purified by flashchromatography, eluting with EtOAc/Hex/MeOH 9:1:1 with 0.1% H₂O toprovide the title compound. MS APCI (+) m/z 497.4 (M+1) detected.

Example 36

N-(4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2-methoxyethoxy)quinazolin-4-amine

Step A: Preparation of 5-(2-methoxyethoxy)quinazolin-4-ol: To a solutionof 2-methoxyethanol (0.528 ml, 6.70 mmol) in DMA (6 mL) was slowly added514 mg of a 60% dispersion of NaH (0.308 g, 12.8 mmol), and the reactionmixture was stirred at room temperature for 30 minutes.5-Fluoroquinazolin-4(3H)-one (1.0 g, 6.09 mmol) was added and thereaction mixture was heated at 80° C. for 2 hours. The reaction wasconcentrated and the residue was suspended in EtOH (75 mL) and thenfiltered through GF/F paper. The filtrate was concentrated to afford thedesired product as a yellow solid.

Step B: Preparation of 4-chloro-5-(2-methoxyethoxy)quinazoline: Preparedaccording to the method of Example 15 using5-(2-methoxyethoxy)quinazolin-4-ol in place of 4-hydroxyquinazolin-6-ylacetate.

Step C: Preparation ofN-(4-([1,2,4]-triazolo[1,5-a]pyridin-7-yloxy)-3-methylphenyl)-5-(2-methoxyethoxy)quinazolin-4-amine:Prepared according to the method of Example 24 using4-chloro-5-(2-methoxyethoxy)quinazoline in place of4-chloro-6-(2-methoxyethoxy)quinazoline. MS APCI (+) m/z 443.1 (M+1)detected.

The following compounds were also prepared according to theabove-described methods.

Ex. # Structure MS m/z 37

511.5 (M + 1) detected 38

443.3 (M + 1) detected 39

443.3 (M + 1) detected 40

442.1 (M + 1) detected 41

522.3 (M + 1) detected 42

435.4 (M + 1) detected 43

418.4 (M + 1) detected 44

514.1 (M + 1) detected 45

516.1 (M + 1) detected 46

518.3 (M + 1) detected 47

455.2 (M + 1) detected 48

498.0 (M + 1) detected 49

496 (M + 1) detected 50

538.3 (M + 1) detected 51

556.2 (M + 1) detected 52

539.2 (M + 1) detected 53

510.0 (M + 1) detected 54

429.3 (M + 1) detected 55

451.0 (M + 1) detected 56

510.1 (M + 1) detected 57

497.0 (M + 1) detected 58

476.1 (M + 1) detected 59

476.3 (M + 1) detected 60

443.3 (M + 1) detected 61

463.3 (M + 1) detected 62

509.0 (M + 1) detected 63

413.3 (M + 1) detected 64

459.1 (M + 1) detected 65

443.0 (M + 1) detected 66

488.2 (M + 1) detected 67

523.0 (M + 1) detected 68

494.1 (M + 1) detected 69

519.3 (M + 1) detected 70

467.3 (M + 1) detected 71

457.3 (M + 1) detected 72

523.3 (M + 1) detected 73

463.2 (M + 1) detected 74

513.2 (M + 1) detected 75

432.4 (M + 1) detected 76

476.0 (M + 1) detected 77

447.3 (M + 1) detected 78

467.3 (M + 1) detected 79

481.1 (M + 1) detected 80

443.3 (M + 1) detected 81

503.2 (M + 1) detected 82

443.3 (M + 1) detected 83

459.2 (M + 1) detected 84

428.1 (M + 1) detected 85

499.3 (M + 1) detected 86

496.3 (M + 1) detected 87

535.3 (M + 1) detected 88

498.3 (M + 1) detected 89

474.3 (M + 1) detected 90

475.2 (M + 1) detected 91

500.2 (M + 1) detected 92

472.4 (M + 1) detected 93

498.2 (M + 1) detected 94

501.3 (M + 1) detected 95

508.3 (M + 1) detected 96

526.2 (M + 1) detected 97

545.1 (M + 1) detected 98

524.4 (M + 1) detected 99

524.2 (M + 1) detected 100

572.2 (M + 1) detected 101

529.3 (M + 1) detected 102

545.3 (M + 1) detected 103

455.2 (M + 1) detected 104

480.1 (M + 1) detected 105

481.3 (M + 1) detected 106

443.0 (M + 1) detected 107

476.4 (M + 1) detected 108

506.3 (M + 1) detected 109

481.3 (M + 1) detected 110

429.3 (M + 1) detected 111

443.1 (M + 1) detected 112

463.1 (M + 1) detected 113

454.1 (M + 1) detected 114

437.4 (M + 1) detected 115

467.2 (M + 1) detected 116

483.3 (M + 1) detected 117

466.4 (M + 1) detected 118

481.3 (M + 1) detected 119

481.4 (M + 1) detected 120

451.4 (M + 1) detected 121

453.3 (M + 1) detected 122

453.4 (M + 1) detected 123

465.2 (M + 1) detected 124

495.3 (M + 1) detected 125

469.2 (M + 1) detected 126

466.3 (M + 1) detected 127

523.3 (M + 1) detected 128

439.4 (M + 1) detected 129

455.4 (M + 1) detected 130

494.3 (M + 1) detected 131

483.2 (M + 1) detected 132

444.1 (M + 1) detected 133

428.4 (M + 1) detected 134

439.3 (M + 1) detected 135

469.2 (M + 1) detected 136

468.3 (M + 1) detected 137

452.4 (M + 1) detected 138

398.3 (M + 1) detected 139

469.3 (M + 1) detected 140

460.3 (M + 1) detected 141

469.3 (M + 1) detected 142

495.2 (M + 1) detected 143

497.3 (M + 1) detected 144

469.2 (M + 1) detected 145

467.4 (M + 1) detected 146

454.4 (M + 1) detected 147

484.3 (M + 1) detected 148

429.3 (M + 1) detected 149

454.4 (M + 1) detected 150

484.1 (M + 1) detected 151

482.3 (M + 1) detected 152

429.3 (M + 1) detected 153

524.2 (M + 1) detected 154

452.4 (M + 1) detected 155

479.2 (M + 1) detected 156

440.2 (M + 1) detected 157

470.3 (M + 1) detected 158

472.1 (M + 1) detected 159

455.1 (M + 1) detected 160

453.4 (M + 1) detected 161

413.2 (M + 1) detected 162

456.2 (M + 1) detected 163

467.3 (M + 1) detected 164

445.1 (M + 1) detected 165

496.4 (M + 1) detected 166

496.2 (M + 1) detected 167

439.2 (M + 1) detected 168

466.3 (M + 1) detected 169

438.4 (M + 1) detected 170

495.2 (M + 1) detected 171

461.3 (M + 1) detected 172

497.1 (M + 1) detected 173

497.3 (M + 1) detected 174

469.3 (M + 1) detected 175

482.2 (M + 1) detected 176

480.4 (M + 1) detected 177

471.3 (M + 1) detected 178

509.2 (M + 1) detected 179

495.3 (M + 1) detected 180

467.3 (M + 1) detected 181

474.3 (M + 1) detected 182

537.3 (M + 1) detected 183

480.2 (M + 1) detected 184

468.1 (M + 1) detected 185

451.3 (M + 1) detected 186

466.3 (M + 1) detected 187

483.3 (M + 1) detected 188

465.4 (M + 1) detected 189

458.1 (M + 1) detected 190

442.3 (M + 1) detected 191

483.3 (M + 1) detected 192

453.3 (M + 1) detected 193

509.5 (M + 1) detected 194

443.3 (M + 1) detected 195

498.3 (M + 1) detected 196

472.2 (M + 1) detected 197

442.2 (M + 1) detected 198

456.2 (M + 1) detected 199

486.2 (M + 1) detected 200

500.2 (M + 1) detected 201

412.3 (M + 1) detected 202

469.3 (M + 1) detected 203

471.3 (M + 1) detected 204

442.3 (M + 1) detected 205

470.3 (M + 1) detected 206

459.3 (M + 1) detected 207

459.2 (M + 1) detected 208

479.3 (M + 1) detected 209

478.2 (M + 1) detected 210

454.1 (M + 1) detected 211

454.2 (M + 1) detected 212

531.2 (M + 1) detected 213

467.3 (M + 1) detected 214

495.2 (M + 1) detected 215

509.3 (M + 1) detected 216

510.1 (M + 1) detected 217

524.2 (M + 1) detected 218

479.2 (M + 1) detected 219

455.2 (M + 1) detected 220

455.2 (M + 1) detected 221

525.2 (M + 1) detected 222

532.2 (M + 1) detected 223

496.3 (M + 1) detected 224

510.1 (M + 1) detected 225

511.2 (M + 1) detected 226

525.3 (M + 1) detected 227

492.2 (M + 1) detected 228

412.2 (M + 1) detected 229

480.2 (M + 1) detected 230

482.2 (M + 1) detected 231

496.3 (M + 1) detected 232

482.3 (M + 1) detected 233

468.2 (M + 1) detected 234

468.2 (M + 1) detected 235

481.1 (M + 1) detected 236

545.1 (M + 1) detected 237

538.2 (M + 1) detected 238

469.2 (M + 1) detected 239

483.2 (M + 1) detected 240

511.1 (M + 1) detected 241

523.2 (M + 1) detected 242

524.1 (M + 1) detected 243

538.2 (M + 1) detected 244

486.1 (M + 1) detected 245

504.3 (M + 1) detected 246

456.4 (M + 1) detected 247

426.4 (M + 1) detected 248

384.4 (M + 1) detected 249

570.0 (M + 1) detected 250

549.2 (M + 1) detected 251

459.4 (M + 1) detected 252

459.4 (M + 1) detected 253

518.3 (M + 1) detected 254

470.3 (M + 1) detected 255

538.2, 540.2 (M+, Cl pattern) detected 256

454.3 (M + 1) detected 257

499.2 (M + 1) detected 258

456.3 (M + 1) detected 259

455.2 (M + 1) detected 260

497.3 (M + 1) detected 261

498.1 (M + 1) detected 262

514.1 (M + 1) detected 263

524.0 (M + 1) detected 264

469.2 (M + 1) detected 265

469.2 (M + 1) detected 266

480.2 (M + 1) detected 267

499.1 (M + 1) detected 268

470.2 (M + 1) detected 269

453.3 (M + 1) detected 270

441.2 (M + 1) detected 271

462.2, 464.2 (M+, Cl pattern) detected 272

446.2 (M + 1) detected 273

476.2, 478.1 (M+, Cl pattern) detected 274

456.3 (M + 1) detected 275

522.1, 520.2 (M+, Br pattern) detected 276

460.4 (M + 1) detected 277

507.3 (M + 1) detected 278

493.3 (M + 1) detected 279

512.1 (M + 1) detected 280

510.1 (M + 1) detected 281

472.2 (M + 1) detected

The foregoing description is considered as illustrative only of theprinciples of the invention. Further, since numerous modifications andchanges will be readily apparent to those skilled in the art, it is notdesired to limit the invention to the exact construction and processshown as described above. Accordingly, all suitable modifications andequivalents may be considered to fall within the scope of the inventionas defined by the claims that follow.

The words “comprise,” “comprising,” “include,” “including,” and“includes” when used in this specification and in the following claimsare intended to specify the presence of stated features, integers,components, or steps, but they do not preclude the presence or additionof one or more other features, integers, components, steps, or groupsthereof.

1. (canceled)
 2. A compound having the structure:

and pharmaceutically acceptable salts thereof.
 3. A compositioncomprising a compound, or its pharmaceutically acceptable salt thereof,according to claim 2 and a pharmaceutically acceptable diluent orcarrier.
 4. A method of treating cancer that over-expresses HER2 in amammal, comprising administering to the mammal a therapeuticallyeffective amount of a compound, or its pharmaceutically acceptable saltthereof, according to claim
 2. 5. The method of claim 4, wherein thecancer is breast cancer.
 6. The method of claim 4, wherein an anti-tumoragent is administered in combination.
 7. The method of claim 6, whereinthe anti-tumor agent is an inhibitor of growth factor.
 8. The method ofclaim 7, wherein the inhibitor of growth factor is trastuzumab.
 9. Themethod of claim 5, wherein an anti-tumor agent is administered incombination.
 10. The method of claim 9, wherein the anti-tumor agent isan inhibitor of growth factor.
 11. The method of claim 10, wherein theinhibitor of growth factor is trastuzumab.